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Submission: On November 13 via api from US — Scanned from DE
Submission: On November 13 via api from US — Scanned from DE
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<option value="acoustics"> Acoustics </option>
<option value="amh"> Acta Microbiologica Hellenica (AMH) </option>
<option value="actuators"> Actuators </option>
<option value="admsci"> Administrative Sciences </option>
<option value="adolescents"> Adolescents </option>
<option value="arm"> Advances in Respiratory Medicine (ARM) </option>
<option value="aerobiology"> Aerobiology </option>
<option value="aerospace"> Aerospace </option>
<option value="agriculture"> Agriculture </option>
<option value="agriengineering"> AgriEngineering </option>
<option value="agrochemicals"> Agrochemicals </option>
<option value="agronomy"> Agronomy </option>
<option value="ai"> AI </option>
<option value="air"> Air </option>
<option value="algorithms"> Algorithms </option>
<option value="allergies"> Allergies </option>
<option value="alloys"> Alloys </option>
<option value="analytica"> Analytica </option>
<option value="analytics"> Analytics </option>
<option value="anatomia"> Anatomia </option>
<option value="anesthres"> Anesthesia Research </option>
<option value="animals"> Animals </option>
<option value="antibiotics"> Antibiotics </option>
<option value="antibodies"> Antibodies </option>
<option value="antioxidants"> Antioxidants </option>
<option value="applbiosci"> Applied Biosciences </option>
<option value="applmech"> Applied Mechanics </option>
<option value="applmicrobiol"> Applied Microbiology </option>
<option value="applnano"> Applied Nano </option>
<option value="applsci"> Applied Sciences </option>
<option value="asi"> Applied System Innovation (ASI) </option>
<option value="appliedchem"> AppliedChem </option>
<option value="appliedmath"> AppliedMath </option>
<option value="aquacj"> Aquaculture Journal </option>
<option value="architecture"> Architecture </option>
<option value="arthropoda"> Arthropoda </option>
<option value="arts"> Arts </option>
<option value="astronomy"> Astronomy </option>
<option value="atmosphere"> Atmosphere </option>
<option value="atoms"> Atoms </option>
<option value="audiolres"> Audiology Research </option>
<option value="automation"> Automation </option>
<option value="axioms"> Axioms </option>
<option value="bacteria"> Bacteria </option>
<option value="batteries"> Batteries </option>
<option value="behavsci"> Behavioral Sciences </option>
<option value="beverages"> Beverages </option>
<option value="BDCC"> Big Data and Cognitive Computing (BDCC) </option>
<option value="biochem"> BioChem </option>
<option value="bioengineering"> Bioengineering </option>
<option value="biologics"> Biologics </option>
<option value="biology"> Biology </option>
<option value="blsf"> Biology and Life Sciences Forum </option>
<option value="biomass"> Biomass </option>
<option value="biomechanics"> Biomechanics </option>
<option value="biomed"> BioMed </option>
<option value="biomedicines"> Biomedicines </option>
<option value="biomedinformatics"> BioMedInformatics </option>
<option value="biomimetics"> Biomimetics </option>
<option value="biomolecules"> Biomolecules </option>
<option value="biophysica"> Biophysica </option>
<option value="biosensors"> Biosensors </option>
<option value="biotech"> BioTech </option>
<option value="birds"> Birds </option>
<option value="blockchains"> Blockchains </option>
<option value="brainsci"> Brain Sciences </option>
<option value="buildings"> Buildings </option>
<option value="businesses"> Businesses </option>
<option value="carbon"> C </option>
<option value="cancers"> Cancers </option>
<option value="cardiogenetics"> Cardiogenetics </option>
<option value="catalysts"> Catalysts </option>
<option value="cells"> Cells </option>
<option value="ceramics"> Ceramics </option>
<option value="challenges"> Challenges </option>
<option value="ChemEngineering"> ChemEngineering </option>
<option value="chemistry"> Chemistry </option>
<option value="chemproc"> Chemistry Proceedings </option>
<option value="chemosensors"> Chemosensors </option>
<option value="children"> Children </option>
<option value="chips"> Chips </option>
<option value="civileng"> CivilEng </option>
<option value="cleantechnol"> Clean Technologies (Clean Technol.) </option>
<option value="climate"> Climate </option>
<option value="ctn"> Clinical and Translational Neuroscience (CTN) </option>
<option value="clinbioenerg"> Clinical Bioenergetics </option>
<option value="clinpract"> Clinics and Practice </option>
<option value="clockssleep"> Clocks & Sleep </option>
<option value="coasts"> Coasts </option>
<option value="coatings"> Coatings </option>
<option value="colloids"> Colloids and Interfaces </option>
<option value="colorants"> Colorants </option>
<option value="commodities"> Commodities </option>
<option value="complications"> Complications </option>
<option value="compounds"> Compounds </option>
<option value="computation"> Computation </option>
<option value="csmf"> Computer Sciences & Mathematics Forum </option>
<option value="computers"> Computers </option>
<option value="condensedmatter"> Condensed Matter </option>
<option value="conservation"> Conservation </option>
<option value="constrmater"> Construction Materials </option>
<option value="cmd"> Corrosion and Materials Degradation (CMD) </option>
<option value="cosmetics"> Cosmetics </option>
<option value="covid"> COVID </option>
<option value="crops"> Crops </option>
<option value="cryo"> Cryo </option>
<option value="cryptography"> Cryptography </option>
<option value="crystals"> Crystals </option>
<option value="cimb"> Current Issues in Molecular Biology (CIMB) </option>
<option value="curroncol"> Current Oncology </option>
<option value="dairy"> Dairy </option>
<option value="data"> Data </option>
<option value="dentistry"> Dentistry Journal </option>
<option value="dermato"> Dermato </option>
<option value="dermatopathology"> Dermatopathology </option>
<option value="designs"> Designs </option>
<option value="diabetology"> Diabetology </option>
<option value="diagnostics"> Diagnostics </option>
<option value="dietetics"> Dietetics </option>
<option value="digital"> Digital </option>
<option value="disabilities"> Disabilities </option>
<option value="diseases"> Diseases </option>
<option value="diversity"> Diversity </option>
<option value="dna"> DNA </option>
<option value="drones"> Drones </option>
<option value="ddc"> Drugs and Drug Candidates (DDC) </option>
<option value="dynamics"> Dynamics </option>
<option value="earth"> Earth </option>
<option value="ecologies"> Ecologies </option>
<option value="econometrics"> Econometrics </option>
<option value="economies"> Economies </option>
<option value="education"> Education Sciences </option>
<option value="electricity"> Electricity </option>
<option value="electrochem"> Electrochem </option>
<option value="electronicmat"> Electronic Materials </option>
<option value="electronics"> Electronics </option>
<option value="ecm"> Emergency Care and Medicine </option>
<option value="encyclopedia"> Encyclopedia </option>
<option value="endocrines"> Endocrines </option>
<option value="energies"> Energies </option>
<option value="esa"> Energy Storage and Applications (ESA) </option>
<option value="eng"> Eng </option>
<option value="engproc"> Engineering Proceedings </option>
<option value="entropy"> Entropy </option>
<option value="environsciproc"> Environmental Sciences Proceedings </option>
<option value="environments"> Environments </option>
<option value="epidemiologia"> Epidemiologia </option>
<option value="epigenomes"> Epigenomes </option>
<option value="ebj"> European Burn Journal (EBJ) </option>
<option value="ejihpe"> European Journal of Investigation in Health, Psychology and Education (EJIHPE) </option>
<option value="fermentation"> Fermentation </option>
<option value="fibers"> Fibers </option>
<option value="fintech"> FinTech </option>
<option value="fire"> Fire </option>
<option value="fishes"> Fishes </option>
<option value="fluids"> Fluids </option>
<option value="foods"> Foods </option>
<option value="forecasting"> Forecasting </option>
<option value="forensicsci"> Forensic Sciences </option>
<option value="forests"> Forests </option>
<option value="fossstud"> Fossil Studies </option>
<option value="foundations"> Foundations </option>
<option value="fractalfract"> Fractal and Fractional (Fractal Fract) </option>
<option value="fuels"> Fuels </option>
<option value="future"> Future </option>
<option value="futureinternet"> Future Internet </option>
<option value="futurepharmacol"> Future Pharmacology </option>
<option value="futuretransp"> Future Transportation </option>
<option value="galaxies"> Galaxies </option>
<option value="games"> Games </option>
<option value="gases"> Gases </option>
<option value="gastroent" selected="selected"> Gastroenterology Insights </option>
<option value="gastrointestdisord"> Gastrointestinal Disorders </option>
<option value="gastronomy"> Gastronomy </option>
<option value="gels"> Gels </option>
<option value="genealogy"> Genealogy </option>
<option value="genes"> Genes </option>
<option value="geographies"> Geographies </option>
<option value="geohazards"> GeoHazards </option>
<option value="geomatics"> Geomatics </option>
<option value="geometry"> Geometry </option>
<option value="geosciences"> Geosciences </option>
<option value="geotechnics"> Geotechnics </option>
<option value="geriatrics"> Geriatrics </option>
<option value="glacies"> Glacies </option>
<option value="gucdd"> Gout, Urate, and Crystal Deposition Disease (GUCDD) </option>
<option value="grasses"> Grasses </option>
<option value="hardware"> Hardware </option>
<option value="healthcare"> Healthcare </option>
<option value="hearts"> Hearts </option>
<option value="hemato"> Hemato </option>
<option value="hematolrep"> Hematology Reports </option>
<option value="heritage"> Heritage </option>
<option value="histories"> Histories </option>
<option value="horticulturae"> Horticulturae </option>
<option value="hospitals"> Hospitals </option>
<option value="humanities"> Humanities </option>
<option value="humans"> Humans </option>
<option value="hydrobiology"> Hydrobiology </option>
<option value="hydrogen"> Hydrogen </option>
<option value="hydrology"> Hydrology </option>
<option value="hygiene"> Hygiene </option>
<option value="immuno"> Immuno </option>
<option value="idr"> Infectious Disease Reports </option>
<option value="informatics"> Informatics </option>
<option value="information"> Information </option>
<option value="infrastructures"> Infrastructures </option>
<option value="inorganics"> Inorganics </option>
<option value="insects"> Insects </option>
<option value="instruments"> Instruments </option>
<option value="iic"> Intelligent Infrastructure and Construction </option>
<option value="ijerph"> International Journal of Environmental Research and Public Health (IJERPH) </option>
<option value="ijfs"> International Journal of Financial Studies (IJFS) </option>
<option value="ijms"> International Journal of Molecular Sciences (IJMS) </option>
<option value="IJNS"> International Journal of Neonatal Screening (IJNS) </option>
<option value="ijpb"> International Journal of Plant Biology (IJPB) </option>
<option value="ijt"> International Journal of Topology </option>
<option value="ijtm"> International Journal of Translational Medicine (IJTM) </option>
<option value="ijtpp"> International Journal of Turbomachinery, Propulsion and Power (IJTPP) </option>
<option value="ime"> International Medical Education (IME) </option>
<option value="inventions"> Inventions </option>
<option value="IoT"> IoT </option>
<option value="ijgi"> ISPRS International Journal of Geo-Information (IJGI) </option>
<option value="J"> J </option>
<option value="jal"> Journal of Ageing and Longevity (JAL) </option>
<option value="jcdd"> Journal of Cardiovascular Development and Disease (JCDD) </option>
<option value="jcto"> Journal of Clinical & Translational Ophthalmology (JCTO) </option>
<option value="jcm"> Journal of Clinical Medicine (JCM) </option>
<option value="jcs"> Journal of Composites Science (J. Compos. Sci.) </option>
<option value="jcp"> Journal of Cybersecurity and Privacy (JCP) </option>
<option value="jdad"> Journal of Dementia and Alzheimer's Disease (JDAD) </option>
<option value="jdb"> Journal of Developmental Biology (JDB) </option>
<option value="jeta"> Journal of Experimental and Theoretical Analyses (JETA) </option>
<option value="jfb"> Journal of Functional Biomaterials (JFB) </option>
<option value="jfmk"> Journal of Functional Morphology and Kinesiology (JFMK) </option>
<option value="jof"> Journal of Fungi (JoF) </option>
<option value="jimaging"> Journal of Imaging (J. Imaging) </option>
<option value="jintelligence"> Journal of Intelligence (J. Intell.) </option>
<option value="jlpea"> Journal of Low Power Electronics and Applications (JLPEA) </option>
<option value="jmmp"> Journal of Manufacturing and Materials Processing (JMMP) </option>
<option value="jmse"> Journal of Marine Science and Engineering (JMSE) </option>
<option value="jmahp"> Journal of Market Access & Health Policy (JMAHP) </option>
<option value="jmp"> Journal of Molecular Pathology (JMP) </option>
<option value="jnt"> Journal of Nanotheranostics (JNT) </option>
<option value="jne"> Journal of Nuclear Engineering (JNE) </option>
<option value="ohbm"> Journal of Otorhinolaryngology, Hearing and Balance Medicine (JOHBM) </option>
<option value="jop"> Journal of Parks </option>
<option value="jpm"> Journal of Personalized Medicine (JPM) </option>
<option value="jpbi"> Journal of Pharmaceutical and BioTech Industry (JPBI) </option>
<option value="jor"> Journal of Respiration (JoR) </option>
<option value="jrfm"> Journal of Risk and Financial Management (JRFM) </option>
<option value="jsan"> Journal of Sensor and Actuator Networks (JSAN) </option>
<option value="joma"> Journal of the Oman Medical Association (JOMA) </option>
<option value="jtaer"> Journal of Theoretical and Applied Electronic Commerce Research (JTAER) </option>
<option value="jvd"> Journal of Vascular Diseases (JVD) </option>
<option value="jox"> Journal of Xenobiotics (JoX) </option>
<option value="jzbg"> Journal of Zoological and Botanical Gardens (JZBG) </option>
<option value="journalmedia"> Journalism and Media </option>
<option value="kidneydial"> Kidney and Dialysis </option>
<option value="kinasesphosphatases"> Kinases and Phosphatases </option>
<option value="knowledge"> Knowledge </option>
<option value="labmed"> LabMed </option>
<option value="laboratories"> Laboratories </option>
<option value="land"> Land </option>
<option value="languages"> Languages </option>
<option value="laws"> Laws </option>
<option value="life"> Life </option>
<option value="limnolrev"> Limnological Review </option>
<option value="lipidology"> Lipidology </option>
<option value="liquids"> Liquids </option>
<option value="literature"> Literature </option>
<option value="livers"> Livers </option>
<option value="logics"> Logics </option>
<option value="logistics"> Logistics </option>
<option value="lubricants"> Lubricants </option>
<option value="lymphatics"> Lymphatics </option>
<option value="make"> Machine Learning and Knowledge Extraction (MAKE) </option>
<option value="machines"> Machines </option>
<option value="macromol"> Macromol </option>
<option value="magnetism"> Magnetism </option>
<option value="magnetochemistry"> Magnetochemistry </option>
<option value="marinedrugs"> Marine Drugs </option>
<option value="materials"> Materials </option>
<option value="materproc"> Materials Proceedings </option>
<option value="mca"> Mathematical and Computational Applications (MCA) </option>
<option value="mathematics"> Mathematics </option>
<option value="medsci"> Medical Sciences </option>
<option value="msf"> Medical Sciences Forum </option>
<option value="medicina"> Medicina </option>
<option value="medicines"> Medicines </option>
<option value="membranes"> Membranes </option>
<option value="merits"> Merits </option>
<option value="metabolites"> Metabolites </option>
<option value="metals"> Metals </option>
<option value="meteorology"> Meteorology </option>
<option value="methane"> Methane </option>
<option value="mps"> Methods and Protocols (MPs) </option>
<option value="metrics"> Metrics </option>
<option value="metrology"> Metrology </option>
<option value="micro"> Micro </option>
<option value="microbiolres"> Microbiology Research </option>
<option value="micromachines"> Micromachines </option>
<option value="microorganisms"> Microorganisms </option>
<option value="microplastics"> Microplastics </option>
<option value="minerals"> Minerals </option>
<option value="mining"> Mining </option>
<option value="modelling"> Modelling </option>
<option value="mmphys"> Modern Mathematical Physics </option>
<option value="molbank"> Molbank </option>
<option value="molecules"> Molecules </option>
<option value="mti"> Multimodal Technologies and Interaction (MTI) </option>
<option value="muscles"> Muscles </option>
<option value="nanoenergyadv"> Nanoenergy Advances </option>
<option value="nanomanufacturing"> Nanomanufacturing </option>
<option value="nanomaterials"> Nanomaterials </option>
<option value="ndt"> NDT </option>
<option value="network"> Network </option>
<option value="neuroglia"> Neuroglia </option>
<option value="neurolint"> Neurology International </option>
<option value="neurosci"> NeuroSci </option>
<option value="nitrogen"> Nitrogen </option>
<option value="ncrna"> Non-Coding RNA (ncRNA) </option>
<option value="nursrep"> Nursing Reports </option>
<option value="nutraceuticals"> Nutraceuticals </option>
<option value="nutrients"> Nutrients </option>
<option value="obesities"> Obesities </option>
<option value="oceans"> Oceans </option>
<option value="onco"> Onco </option>
<option value="optics"> Optics </option>
<option value="oral"> Oral </option>
<option value="organics"> Organics </option>
<option value="organoids"> Organoids </option>
<option value="osteology"> Osteology </option>
<option value="oxygen"> Oxygen </option>
<option value="parasitologia"> Parasitologia </option>
<option value="particles"> Particles </option>
<option value="pathogens"> Pathogens </option>
<option value="pathophysiology"> Pathophysiology </option>
<option value="pediatrrep"> Pediatric Reports </option>
<option value="pets"> Pets </option>
<option value="pharmaceuticals"> Pharmaceuticals </option>
<option value="pharmaceutics"> Pharmaceutics </option>
<option value="pharmacoepidemiology"> Pharmacoepidemiology </option>
<option value="pharmacy"> Pharmacy </option>
<option value="philosophies"> Philosophies </option>
<option value="photochem"> Photochem </option>
<option value="photonics"> Photonics </option>
<option value="phycology"> Phycology </option>
<option value="physchem"> Physchem </option>
<option value="psf"> Physical Sciences Forum </option>
<option value="physics"> Physics </option>
<option value="physiologia"> Physiologia </option>
<option value="plants"> Plants </option>
<option value="plasma"> Plasma </option>
<option value="platforms"> Platforms </option>
<option value="pollutants"> Pollutants </option>
<option value="polymers"> Polymers </option>
<option value="polysaccharides"> Polysaccharides </option>
<option value="populations"> Populations </option>
<option value="poultry"> Poultry </option>
<option value="powders"> Powders </option>
<option value="proceedings"> Proceedings </option>
<option value="processes"> Processes </option>
<option value="prosthesis"> Prosthesis </option>
<option value="proteomes"> Proteomes </option>
<option value="psychiatryint"> Psychiatry International </option>
<option value="psychoactives"> Psychoactives </option>
<option value="psycholint"> Psychology International </option>
<option value="publications"> Publications </option>
<option value="qubs"> Quantum Beam Science (QuBS) </option>
<option value="quantumrep"> Quantum Reports </option>
<option value="quaternary"> Quaternary </option>
<option value="radiation"> Radiation </option>
<option value="reactions"> Reactions </option>
<option value="realestate"> Real Estate </option>
<option value="receptors"> Receptors </option>
<option value="recycling"> Recycling </option>
<option value="rsee"> Regional Science and Environmental Economics (RSEE) </option>
<option value="religions"> Religions </option>
<option value="remotesensing"> Remote Sensing </option>
<option value="reports"> Reports </option>
<option value="reprodmed"> Reproductive Medicine (Reprod. Med.) </option>
<option value="resources"> Resources </option>
<option value="rheumato"> Rheumato </option>
<option value="risks"> Risks </option>
<option value="robotics"> Robotics </option>
<option value="ruminants"> Ruminants </option>
<option value="safety"> Safety </option>
<option value="sci"> Sci </option>
<option value="scipharm"> Scientia Pharmaceutica (Sci. Pharm.) </option>
<option value="sclerosis"> Sclerosis </option>
<option value="seeds"> Seeds </option>
<option value="sensors"> Sensors </option>
<option value="separations"> Separations </option>
<option value="sexes"> Sexes </option>
<option value="signals"> Signals </option>
<option value="sinusitis"> Sinusitis </option>
<option value="smartcities"> Smart Cities </option>
<option value="socsci"> Social Sciences </option>
<option value="siuj"> Société Internationale d’Urologie Journal (SIUJ) </option>
<option value="societies"> Societies </option>
<option value="software"> Software </option>
<option value="soilsystems"> Soil Systems </option>
<option value="solar"> Solar </option>
<option value="solids"> Solids </option>
<option value="spectroscj"> Spectroscopy Journal </option>
<option value="sports"> Sports </option>
<option value="standards"> Standards </option>
<option value="stats"> Stats </option>
<option value="stresses"> Stresses </option>
<option value="surfaces"> Surfaces </option>
<option value="surgeries"> Surgeries </option>
<option value="std"> Surgical Techniques Development </option>
<option value="sustainability"> Sustainability </option>
<option value="suschem"> Sustainable Chemistry </option>
<option value="symmetry"> Symmetry </option>
<option value="synbio"> SynBio </option>
<option value="systems"> Systems </option>
<option value="targets"> Targets </option>
<option value="taxonomy"> Taxonomy </option>
<option value="technologies"> Technologies </option>
<option value="telecom"> Telecom </option>
<option value="textiles"> Textiles </option>
<option value="thalassrep"> Thalassemia Reports </option>
<option value="therapeutics"> Therapeutics </option>
<option value="thermo"> Thermo </option>
<option value="timespace"> Time and Space </option>
<option value="tomography"> Tomography </option>
<option value="tourismhosp"> Tourism and Hospitality </option>
<option value="toxics"> Toxics </option>
<option value="toxins"> Toxins </option>
<option value="transplantology"> Transplantology </option>
<option value="traumacare"> Trauma Care </option>
<option value="higheredu"> Trends in Higher Education </option>
<option value="tropicalmed"> Tropical Medicine and Infectious Disease (TropicalMed) </option>
<option value="universe"> Universe </option>
<option value="urbansci"> Urban Science </option>
<option value="uro"> Uro </option>
<option value="vaccines"> Vaccines </option>
<option value="vehicles"> Vehicles </option>
<option value="venereology"> Venereology </option>
<option value="vetsci"> Veterinary Sciences </option>
<option value="vibration"> Vibration </option>
<option value="virtualworlds"> Virtual Worlds </option>
<option value="viruses"> Viruses </option>
<option value="vision"> Vision </option>
<option value="waste"> Waste </option>
<option value="water"> Water </option>
<option value="wild"> Wild </option>
<option value="wind"> Wind </option>
<option value="women"> Women </option>
<option value="world"> World </option>
<option value="wevj"> World Electric Vehicle Journal (WEVJ) </option>
<option value="youth"> Youth </option>
<option value="zoonoticdis"> Zoonotic Diseases </option>
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<option value="applnano">Applied Nano</option>
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<option value="asi">Applied System Innovation</option>
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<option value="aquacj">Aquaculture Journal</option>
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<option value="automation">Automation</option>
<option value="axioms">Axioms</option>
<option value="bacteria">Bacteria</option>
<option value="batteries">Batteries</option>
<option value="behavsci">Behavioral Sciences</option>
<option value="beverages">Beverages</option>
<option value="BDCC">Big Data and Cognitive Computing</option>
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<option value="bioengineering">Bioengineering</option>
<option value="biologics">Biologics</option>
<option value="biology">Biology</option>
<option value="blsf">Biology and Life Sciences Forum</option>
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<option value="biomolecules">Biomolecules</option>
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<option value="birds">Birds</option>
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<option value="buildings">Buildings</option>
<option value="businesses">Businesses</option>
<option value="carbon">C</option>
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<option value="catalysts">Catalysts</option>
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<option value="challenges">Challenges</option>
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<option value="chemproc">Chemistry Proceedings</option>
<option value="chemosensors">Chemosensors</option>
<option value="children">Children</option>
<option value="chips">Chips</option>
<option value="civileng">CivilEng</option>
<option value="cleantechnol">Clean Technologies</option>
<option value="climate">Climate</option>
<option value="ctn">Clinical and Translational Neuroscience</option>
<option value="clinbioenerg">Clinical Bioenergetics</option>
<option value="clinpract">Clinics and Practice</option>
<option value="clockssleep">Clocks & Sleep</option>
<option value="coasts">Coasts</option>
<option value="coatings">Coatings</option>
<option value="colloids">Colloids and Interfaces</option>
<option value="colorants">Colorants</option>
<option value="commodities">Commodities</option>
<option value="complications">Complications</option>
<option value="compounds">Compounds</option>
<option value="computation">Computation</option>
<option value="csmf">Computer Sciences & Mathematics Forum</option>
<option value="computers">Computers</option>
<option value="condensedmatter">Condensed Matter</option>
<option value="conservation">Conservation</option>
<option value="constrmater">Construction Materials</option>
<option value="cmd">Corrosion and Materials Degradation</option>
<option value="cosmetics">Cosmetics</option>
<option value="covid">COVID</option>
<option value="crops">Crops</option>
<option value="cryo">Cryo</option>
<option value="cryptography">Cryptography</option>
<option value="crystals">Crystals</option>
<option value="cimb">Current Issues in Molecular Biology</option>
<option value="curroncol">Current Oncology</option>
<option value="dairy">Dairy</option>
<option value="data">Data</option>
<option value="dentistry">Dentistry Journal</option>
<option value="dermato">Dermato</option>
<option value="dermatopathology">Dermatopathology</option>
<option value="designs">Designs</option>
<option value="diabetology">Diabetology</option>
<option value="diagnostics">Diagnostics</option>
<option value="dietetics">Dietetics</option>
<option value="digital">Digital</option>
<option value="disabilities">Disabilities</option>
<option value="diseases">Diseases</option>
<option value="diversity">Diversity</option>
<option value="dna">DNA</option>
<option value="drones">Drones</option>
<option value="ddc">Drugs and Drug Candidates</option>
<option value="dynamics">Dynamics</option>
<option value="earth">Earth</option>
<option value="ecologies">Ecologies</option>
<option value="econometrics">Econometrics</option>
<option value="economies">Economies</option>
<option value="education">Education Sciences</option>
<option value="electricity">Electricity</option>
<option value="electrochem">Electrochem</option>
<option value="electronicmat">Electronic Materials</option>
<option value="electronics">Electronics</option>
<option value="ecm">Emergency Care and Medicine</option>
<option value="encyclopedia">Encyclopedia</option>
<option value="endocrines">Endocrines</option>
<option value="energies">Energies</option>
<option value="esa">Energy Storage and Applications</option>
<option value="eng">Eng</option>
<option value="engproc">Engineering Proceedings</option>
<option value="entropy">Entropy</option>
<option value="environsciproc">Environmental Sciences Proceedings</option>
<option value="environments">Environments</option>
<option value="epidemiologia">Epidemiologia</option>
<option value="epigenomes">Epigenomes</option>
<option value="ebj">European Burn Journal</option>
<option value="ejihpe">European Journal of Investigation in Health, Psychology and Education</option>
<option value="fermentation">Fermentation</option>
<option value="fibers">Fibers</option>
<option value="fintech">FinTech</option>
<option value="fire">Fire</option>
<option value="fishes">Fishes</option>
<option value="fluids">Fluids</option>
<option value="foods">Foods</option>
<option value="forecasting">Forecasting</option>
<option value="forensicsci">Forensic Sciences</option>
<option value="forests">Forests</option>
<option value="fossstud">Fossil Studies</option>
<option value="foundations">Foundations</option>
<option value="fractalfract">Fractal and Fractional</option>
<option value="fuels">Fuels</option>
<option value="future">Future</option>
<option value="futureinternet">Future Internet</option>
<option value="futurepharmacol">Future Pharmacology</option>
<option value="futuretransp">Future Transportation</option>
<option value="galaxies">Galaxies</option>
<option value="games">Games</option>
<option value="gases">Gases</option>
<option value="gastroent">Gastroenterology Insights</option>
<option value="gastrointestdisord">Gastrointestinal Disorders</option>
<option value="gastronomy">Gastronomy</option>
<option value="gels">Gels</option>
<option value="genealogy">Genealogy</option>
<option value="genes">Genes</option>
<option value="geographies">Geographies</option>
<option value="geohazards">GeoHazards</option>
<option value="geomatics">Geomatics</option>
<option value="geometry">Geometry</option>
<option value="geosciences">Geosciences</option>
<option value="geotechnics">Geotechnics</option>
<option value="geriatrics">Geriatrics</option>
<option value="glacies">Glacies</option>
<option value="gucdd">Gout, Urate, and Crystal Deposition Disease</option>
<option value="grasses">Grasses</option>
<option value="hardware">Hardware</option>
<option value="healthcare">Healthcare</option>
<option value="hearts">Hearts</option>
<option value="hemato">Hemato</option>
<option value="hematolrep">Hematology Reports</option>
<option value="heritage">Heritage</option>
<option value="histories">Histories</option>
<option value="horticulturae">Horticulturae</option>
<option value="hospitals">Hospitals</option>
<option value="humanities">Humanities</option>
<option value="humans">Humans</option>
<option value="hydrobiology">Hydrobiology</option>
<option value="hydrogen">Hydrogen</option>
<option value="hydrology">Hydrology</option>
<option value="hygiene">Hygiene</option>
<option value="immuno">Immuno</option>
<option value="idr">Infectious Disease Reports</option>
<option value="informatics">Informatics</option>
<option value="information">Information</option>
<option value="infrastructures">Infrastructures</option>
<option value="inorganics">Inorganics</option>
<option value="insects">Insects</option>
<option value="instruments">Instruments</option>
<option value="iic">Intelligent Infrastructure and Construction</option>
<option value="ijerph">International Journal of Environmental Research and Public Health</option>
<option value="ijfs">International Journal of Financial Studies</option>
<option value="ijms">International Journal of Molecular Sciences</option>
<option value="IJNS">International Journal of Neonatal Screening</option>
<option value="ijpb">International Journal of Plant Biology</option>
<option value="ijt">International Journal of Topology</option>
<option value="ijtm">International Journal of Translational Medicine</option>
<option value="ijtpp">International Journal of Turbomachinery, Propulsion and Power</option>
<option value="ime">International Medical Education</option>
<option value="inventions">Inventions</option>
<option value="IoT">IoT</option>
<option value="ijgi">ISPRS International Journal of Geo-Information</option>
<option value="J">J</option>
<option value="jal">Journal of Ageing and Longevity</option>
<option value="jcdd">Journal of Cardiovascular Development and Disease</option>
<option value="jcto">Journal of Clinical & Translational Ophthalmology</option>
<option value="jcm">Journal of Clinical Medicine</option>
<option value="jcs">Journal of Composites Science</option>
<option value="jcp">Journal of Cybersecurity and Privacy</option>
<option value="jdad">Journal of Dementia and Alzheimer's Disease</option>
<option value="jdb">Journal of Developmental Biology</option>
<option value="jeta">Journal of Experimental and Theoretical Analyses</option>
<option value="jfb">Journal of Functional Biomaterials</option>
<option value="jfmk">Journal of Functional Morphology and Kinesiology</option>
<option value="jof">Journal of Fungi</option>
<option value="jimaging">Journal of Imaging</option>
<option value="jintelligence">Journal of Intelligence</option>
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* Table of Contents
* Abstract
* Introduction
* A Brief Overview of Autophagy
* Pathogenesis of Acute Pancreatitis
* Chronic Pancreatitis
* A Brief Synopsis of Forms of Cellular Death in Acute and Chronic
Pancreatitis
* Autophagy in Pancreatitis
* Future Perspectives
* Conclusions
* Author Contributions
* Funding
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Open AccessReview
THE PATHOGENESIS OF PANCREATITIS AND THE ROLE OF AUTOPHAGY
by
Ioannis Tsomidis
Ioannis Tsomidis
SciProfiles Scilit Preprints.org Google Scholar
1,*,
Argyro Voumvouraki
Argyro Voumvouraki
SciProfiles Scilit Preprints.org Google Scholar
2 and
Elias Kouroumalis
Elias Kouroumalis
SciProfiles Scilit Preprints.org Google Scholar
1
1
Laboratory of Gastroenterology and Hepatology, University of Crete Medical
School, 71500 Heraklion, Crete, Greece
2
1st Department of Internal Medicine, AHEPA University Hospital, 54621
Thessaloniki, Greece
*
Author to whom correspondence should be addressed.
Gastroenterol. Insights 2024, 15(2), 303-341;
https://doi.org/10.3390/gastroent15020022
Submission received: 9 March 2024 / Revised: 31 March 2024 / Accepted: 9 April
2024 / Published: 22 April 2024
(This article belongs to the Special Issue Recent Advances in the Management of
Gastrointestinal Disorders)
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ABSTRACT
The pathogenesis of acute and chronic pancreatitis has recently evolved as new
findings demonstrate a complex mechanism operating through various pathways. In
this review, the current evidence indicating that several mechanisms act in
concert to induce and perpetuate pancreatitis were presented. As autophagy is
now considered a fundamental mechanism in the pathophysiology of both acute and
chronic pancreatitis, the fundamentals of the autophagy pathway were discussed
to allow for a better understanding of the pathophysiological mechanisms of
pancreatitis. The various aspects of pathogenesis, including trypsinogen
activation, ER stress and mitochondrial dysfunction, the implications of
inflammation, and macrophage involvement in innate immunity, as well as the
significance of pancreatic stellate cells in the development of fibrosis, were
also analyzed. Recent findings on exosomes and the miRNA regulatory role were
also presented. Finally, the role of autophagy in the protection and aggravation
of pancreatitis and possible therapeutic implications were reviewed.
Keywords:
pancreatitis; autophagy; mitochondrial abnormalities; ER stress; innate
immunity; macrophages; fibrosis
1. INTRODUCTION
The main etiologies of both acute (AP) and chronic pancreatitis (CP) are still
gallstones and prolonged alcohol consumption. Their incidence is closely related
to the prevalence of gallstone disease and alcohol abuse [1]. Alcohol abuse as a
cause of pancreatitis requires consumption of ≥4–5 drinks per day over >5 years
[2].
An additional risk factor is smoking, as several studies support an important
role for either smoking alone or in combination with alcohol abuse [3,4,5]. The
role of hypertriglyceridemia has also been established, as this is the third
leading cause of acute pancreatitis [6,7]. It has been reported that
approximately 15–20% of individuals with triglyceride levels over 1000 mg/dL
will develop acute pancreatitis [8]. Other common etiologies of acute
pancreatitis include complications of endoscopic retrograde
cholangiopancreatography and autoimmunity, while in a small proportion of cases,
no obvious factors can be identified and the term idiopathic pancreatitis is
used [1,9]. Diabetes has been associated with an increased risk for pancreatitis
[10,11,12]. Finally, medication-related pancreatitis is not a common cause,
accounting for fewer than 5% of cases [13]. Drugs strongly associated with acute
pancreatitis include azathioprine, 6-mercaptopurine, didanosine, valproic acid,
angiotensin-converting enzyme inhibitors, and mesalamine [13].
A distinct group are patients where the first episodes of acute pancreatitis
appear before the age of 35. Genetic abnormalities are found in nearly half of
them [14]. Interestingly, a genetic mutation in claudin 2 may synergize with
alcohol consumption in the development of pancreatitis, indicating the interplay
between external and genetic factors in the pathogenesis of pancreatitis
[15,16].
Chronic pancreatitis develops in about 10% of patients after the first episode
of AP and in about 30% of patients with recurrent AP. Male sex and alcohol abuse
are significant risk factors for the transition from AP to CP [17]. Chronic
inflammation of the pancreas is caused by acinar and ductular cell injury driven
by alcohol, smoking, hypercalcemia, genetic factors, or any combination of the
above. It is distinguished from autoimmune CP, which responds to steroid
treatment, obstructive CP, and infectious CP. Classic CP can be dominated either
by fibrosis or by atrophy [18,19,20]. The relationship of ethanol and smoking to
CP has been unequivocally proved. The amount and duration of ethanol consumption
have been estimated to be either a median of 5.1 drinks/d or a consumption of up
to 110–277 g ethanol/d over 5–25 years, similarly to AP [21,22,23,24,25]. As in
AP, a synergy among genetic, immune, and environmental factors may be important
[26,27,28,29,30]. Interestingly, post-mortem pathological studies of chronic
alcoholics without a previous AP event in their medical history showed the
presence of fibrosis and/or ductal calcifications in 47–68% of cases, indicating
extensive CP that escaped undiagnosed [25,31,32].
The pathogenesis of both AP and CP is a complex process with many points that
have not been fully investigated. Several mechanisms have been incriminated,
such as acinar cell auto-digestion, mitochondrial abnormalities, and the
involvement of immunity and inflammation. Recently, the role of autophagy has
been recognized but not yet fully investigated. Therefore, in this review, we
report an outline of the pathophysiology of pancreatitis, with a detailed
presentation of the role of autophagy.
2. A BRIEF OVERVIEW OF AUTOPHAGY
Autophagy is a degradation pathway that allows for the disposition of
intracellular waste material including damaged organelles or intracellular
pathogens. After lysosomal degradation, most of the final products can be
recycled and re-used, supporting the energy system of the cell.
Τhe term autophagy (a Greek word for self-eating) was introduced by Anselmier
[33]. The modern concept of autophagy, however, started with the pioneer work of
Christian René de Duve in the 1950s, when acid-phosphatase-positive granules
were identified in the rat liver [34] and the term lysosome appeared for the
first time [35]. The next important step came when the group of Oshumi described
a series of fifteen autophagy-related genes (Atgs) involved in Saccharomyces
cerevisiae autophagy [36]. Today, more than 40 Atgs have been identified [37].
The importance of autophagy led to the awarding of two Nobel Prizes for
Physiology or Medicine, the first to Christian De Duve in 1974 and the second to
Yoshinori Ohsumi in 2016 [38]. Historical landmarks of autophagy have been
described by Ohsumi [39].
There are several stages in the pathway of autophagy. The initiation stage is
followed by the elongation of the phagophore and the autophagosome formation,
followed by fusion with lysosomes and degradation of cellular organelles,
proteins, and lipids.
Initiation stage and phagophore formation. Autophagy inducers are responsible
for the initiation stage. In reality, autophagy is a series of phosphorylations
and de-phosphorylations [40]. Three kinases are the main regulators of
autophagy, namely the mammalian target of rapamycin (mTOR), the Unc-51 like
autophagy activating kinase (ULK1), and the AMP-dependent protein kinase (AMPK)
[41]. Autophagy inducers, such as starvation and increased levels of reactive
oxygen species (ROS), repress mTOR and activate AMPK, which results in ULK1
activation [42]. Phosphorylation of ULK1 by mTOR reduces its activity, thus
decreasing autophagy, while phosphorylation by the AMPK at a different site
activates ULK1 and autophagy [43]. Upon induction of autophagy, the ULK1 complex
is formed from the assembly of the ULK1, ATG13, FIP200, and ATG101 proteins
[44,45]. Autophagy is also upregulated by p38 through inhibition of mTOR, while
c-Jun N-terminal kinase1 (JNK1) and BNIP3 (BCL2/adenovirus E1B 19 kDa
protein-interacting protein 3) disrupt the B-cell lymphoma 2 (Bcl-2)–Beclin1
complex, inducing autophagy [46,47]. Free Beclin1 binds to Vps34-Vps15 to
increase autophagy through the formation of the class III PI3K kinase complex
(PI3KC3), consisting of Vps34-Vps15-Beclin1 [48,49]. These complexes lead to the
formation of the autophagosome. Then, Vps34 produces
phosphatidylinositol-3-phosphate to recruit the effector protein DFCP1, which
promotes the development of the double membrane phagophore [50]. The phagophore
is generated from the endoplasmic reticulum (ER) or Golgi membranes,
mitochondria, and plasma membrane via endocytosis mediated by clathrin.
There are some additional points in the regulation of the initial stages of
autophagy. AMPK can negatively regulate mTORC1, either directly through the
phosphorylation of mTORC1 activity or indirectly by activating TSC2, which is a
strong inhibitor of mTORC1 [51]. Recently, an additional mechanism for mTORC1
activation under energy-rich conditions was described. mTORC1 phosphorylates the
protein Pacer, causing the disruption of the complex formed by the proteins
Pacer, Syntaxin17 (Stx17), and the homotypic fusion and vacuole protein sorting
(HOPS), thus inhibiting the autophagosome maturation mediated by this complex
[52,53].
Two additional autophagy regulators have been described. The long non-coding RNA
(lncRNA) NBR2 inhibits Beclin 1-dependent autophagy and attenuates the
autophagy-induced cell proliferation [54], while Forkhead box O3 (FOXO3), a
member of the FOXO subfamily of transcription factors, upregulates autophagy,
acting on ULK1, Beclin-1, and LC3 [55].
Expansion (elongation). ULK1 phosphorylation leads to autophagosome formation.
The critical step is the phosphorylation of ATG13, leading to the formation of
the complex ATG5-ATG12, ATG16L1 [56,57]. This complex and the
phosphatidylethanolamine (PE)-LC3 systems are critical for the elongation of
phagophores [50]. Pro-LC3 cleaved by ATG4B leads to the generation of the
cytosolic form of LC3 (LC3-I). Then, ATG7 processes LC3-I and ATG3 to be
conjugated to PE and form LC3-II. The transformation of phagophores into
autophagosomes requires the ATG12–ATG5–ATG16 complex and the PE-conjugated LC3II
(ATG8) system. Autophagosomes contain materials or cellular organelles destined
for degradation.
Autophagosome fusion to the lysosome. This is the final stage of autophagy that
allows for the autophagy flux. The autophagosome does not contain hydrolases and
the pH is neutral. Fusion with lysosomes forms autolysosomes during the
so-called autophagic flux. Overproduction of autophagosomes faster than the flux
rate or when flux is repressed will increase the levels of LC3 and p62 [58].
Components that are destined to lysosomal degradation are either labeled by
ubiquitin or attached to receptors, such as sequestosome 1 (SQSTM1, also known
as p62), and CALCOCO2 (calcium binding and coiled-coil domain 2). These
receptors interact with LC3 to deliver the component into the autophagosomes
[59,60].
A critical point for fusion to occur is the presence of soluble
N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins
localized in opposing membranes of the particles to be fused. Two SNARE
complexes mediate the fusion of autophagosomes with lysosomes. The first
consists of STX17-SNAP29-VAMP8 [61], and the second is composed of
YKT6-SNAP29-STX7 [62]. For a complete fusion, additional proteins are also
recruited, such as the HOPS complex, baculovirus IAP repeat containing
ubiquitin-conjugating enzyme (BRUCE), and GRASP55, that bind to proteins of the
lysosomal membranes, such as Rab-7 and Monensin sensitivity protein 1—Caffeine,
calcium, and zinc 1 complexes (Mon1-Ccz1) [63]. ATG8 proteins also contribute to
fusion protein recruitment, but they must be removed before final fusion [64].
Rab7 binds to FYCO1 (FYVE and coiled-coil domain-containing 1), ORP1L
(oxysterol-binding protein-related protein 1L), and RILP (Rab-interacting
lysosomal protein). In the next step, SM (Sec1/Munc-18) family proteins
facilitate SNARE complex assembly and zippering. The zippering of these domains
fuses the membranes, and SNAREs are now located on the same membrane [65]. The
autophagosome–lysosome fusion process requires SNARE complex disassembly on
post-fusion membranes [66].
Autophagosome degradation and recycling. After fusion, hydrolases that are
active at acidic pH digest the different constituents. In lysosomes, the
vacuolar ATPase (vATPase) regulates the import of hydrogen ions to maintain the
acidic pH. The same vATPase also induces the transcription factor EB (TFEB).
TFEB is phosphorylated in starvation conditions, translocates to the nucleus,
and induces the transcription of genes that promote autophagy, including LC3 and
p62 [67,68]. mTOR activation decreases TFEB activity, and the autophagic
machinery is repressed [69]. TFEB is also a controller of lysosomal biogenesis
genes [70,71]. TFEB and ZKSCAN3 are major antagonistic factors during autophagy.
ZKSCAN3 is the major transcriptional repressor of autophagy by targeting
biogenesis and fusion of autophagosomes and lysosomes [72,73]. TFEB is also a
controller of inflammation. Reduction of TFEB leads to exacerbation of
inflammation [74]. After degradation, the breakdown products are moved back into
the cytosol by lysosomal transporters and re-utilized by the cell [75].
Non-canonical forms of autophagy were reported as leading to similar fusion
[76]. Several members of the Atg machinery are not used. Rab9-mediated autophagy
functions in cells with atg5 and atg7 deletion. This non-canonical autophagy
does not require ATG8/LC3 but is directly regulated by ULK1 [76]. By contrast,
LAP is another form of non-canonical autophagy that does not require ULK1/2 but
requires ATG8/LC3 conjugation instead and involves ATG5 and ATG7. LAP recruits
LC3-II to the phagosomal membrane [77,78,79] and is taken up by macrophages
through innate immune receptors, such as Toll-like receptors. In contrast to
classical autophagy, the LAPasome is a single membrane vacuole. The term CASM
(conjugation of ATG8 to single membranes) was introduced to describe these
related pathways [80,81,82]. Detailed descriptions of the autophagy pathway have
recently been published [66,83].
Figure 1 summarizes in a simplified diagram the various steps of autophagy.
Figure 1. A simplified diagram of autophagy regulation. Black arrows:
activation. Red arrows: inhibition. Intermittent arrows: cleavage. Certain
pathways have been omitted for clarity. See text for more details. Bcl-2: B-cell
lymphoma-2; FADD: Fas-associating protein with death domain; TRADD: Tumor
necrosis factor receptor type 1-associated DEATH domain protein; RIPK1: Receptor
Interacting Serine/Threonine Kinase 1.
The main regulators of autophagy are three kinases, namely the mammalian target
of rapamycin (mTOR), the Unc-51 like autophagy activating kinase (ULK1), and the
AMP-dependent protein kinase (AMPK). ULK1 and AMPK activation promote autophagy,
while mTOR activation inhibits autophagy. Beclin 1 and Bcl-2 are important
elements in the process. Activation of the TNFR1 leads to caspase 8 activation
that cleaves Beclin 1, and the C-terminal fragment inhibits autophagy. The
cleavage of Atg4D by caspase-3 generates a fragment, which increases autophagy.
The effect of P53 on autophagy depends on localization. Cytoplasmic P53 inhibits
autophagy, while nuclear P53 activates AMPK, increasing autophagy.
2.1. MITOPHAGY
A specialized form of autophagy that is pertinent in pancreatitis is mitophagy.
It selectively degrades damaged mitochondria irrespective of the cause of damage
[84,85]. Mitophagy is induced by two signal pathways, the PINK1 (PTEN-induced
putative kinase 1)-PARKIN (parkin RBR E3 ubiquitin protein ligase) pathway and
the PINK1/PARKIN-independent pathway [86,87]. PINK1 is aggregated into the inner
mitochondrial membrane (IMM) in normal mitochondria through the activity of the
TOM (translocase of the outer mitochondrial membrane) and TIM23 (translocase of
inner mitochondrial membrane 23) proteins. PINK1 is cleaved by PARL
(presenilin-associated rhomboid like). During severe oxidative stress, impaired
mitochondria are not capable of PINK1 seggregation into the IMM. PINK1
associates with TOM and accumulates on the outer mitochondrial membrane (OMM)
[88,89], where it recruits and activates Parkin from the cytoplasm [90]. Parkin
ubiquitinates several OMM proteins, such as mitofusin 1 and mitofusin 2,
voltage-dependent anion channel (VDAC), and Miro [91,92]. Cargo receptor
proteins, such as p62, OPTN (optineurin), and CALCOCO2, bind to these OMM
proteins to start autophagosome formation [91,93] and subsequent fusion with
lysosomes. Mitophagy may be upregulated by phosphorylation of OPTN via the
activation of TBK1 (TANK-binding kinase 1) [94,95].
PINK1/Parkin-independent mitophagy requires interaction of LC3II through the
LC3-interacting region (LIR) with OMM proteins, such as FUN14 domain containing
1 (FUNDC1), NIP3-like protein X (Nix/Bnip3L), and Bcl-2/adenovirus E1B (Bnip3).
The interaction leads damaged mitochondria to the autophagosomes and lysosomal
fusion [86].
Details on mitophagy mechanisms have recently been published [96,97,98,99,100].
There are several other specialized forms of autophagy, but their role in
pancreatitis has not been investigated [86].
2.2. AUTOPHAGY AND IMMUNITY
Autophagy is implicated in the regulation of the immune system [101,102],
particularly in the regulation of innate immunity in macrophages [103,104].
Interestingly, there is evidence that high autophagic activity is implicated in
acquired immunity as well because it maintains the differentiation and function
of regulatory T (Treg)-cells [105] and γ δ T-cells [106].
2.3. AUTOPHAGY AND CELL DEATH
Autophagy is mostly a protective cellular mechanism supporting cell survival.
However, it may turn into a cellular death mechanism through its effect on
apoptosis [107]. Autophagy is tightly related to apoptosis. These two pathways
are affecting each other, being mutually exclusive [108]. Autophagy reduces the
induction of caspase-dependent apoptosis, and apoptosis-associated caspase
activation suppresses the autophagic process. Yet, autophagy may induce
apoptosis or necrosis, while autophagy itself may degrade the cytoplasm, leading
to autophagic cell death [109,110]. The balance between p53 and AKT/mTOR is
crucial for the fate of cells [111]. Autophagy also induces a newly described
mechanism of cell death named ferroptosis [112,113]. Many proteins vital for
autophagy (like ATGs) also participate in ferroptosis. Additionally, activators
of ferroptosis, such as erastin, initiate autophagosome formation, while
activation of autophagy led to ferroptotic death, possibly by increasing ferrous
availability through ferritinophagy [114,115].
2.4. AUTOPHAGY AND INFLAMMATION
Autophagy is also implicated in the inflammatory response. Inflammasomes and
autophagy affect each other. The same inhibitory mechanisms are involved, but
they are regulated by different pathways. Autophagy could either repress the
assembly of the nucleotide-binding oligomerization domain-like receptor family
pyrin domain containing 3 (NLRP3) inflammasome [116] or eliminate active
inflammasomes, particularly in macrophages [117]. In addition, the degradation
of damaged organelles by autophagy does not allow for the production of more
danger-associated molecular patterns (DAMPS) that would further activate NLRP3
inflammasomes [118]. DAMPS activation of NLRP3 leads to pyroptosis through the
activation of procaspase 1 activation followed by the production of IL-1β and
IL-18 [119]. This negative interplay between autophagy and inflammasome can
become positive. Autophagy may induce NLRP3 activation by initiating NF-kB
nuclear translocation, leading to pyroptosis [120,121].
3. PATHOGENESIS OF ACUTE PANCREATITIS
Various pathways have been implicated in the complex pathogenesis of AP. Thus,
pathological calcium signal transduction, mitochondrial dysfunction, premature
activation of trypsinogen in acinar cells and macrophages, endoplasmic reticulum
stress (ERs), unfolded protein reaction (UPR), and autophagy impairment have
been investigated mostly in animal models [122,123]. Earlier experimental
evidence indicated that both acinar cells and ductal cells participate in the
pathogenesis of acute pancreatitis. Recently, exosomes that contain proteins,
nucleic acids, and lipids have been incriminated in the evolution of AP
[124,125].
Abnormalities of intracellular organelles of acinar cells are the basis of the
pathogenesis of acute pancreatitis in close association with abnormalities of
water and electrolyte secretion by the ductular cells [126,127]. Pancreatic
enzyme secretion is blocked in edematous and necrotizing pancreatitis models
[128]. On the other hand, pancreatic fluid secretion is four- to five-fold
increased at the early stages of pancreatitis, indicating that a defense
mechanism is activated to attenuate the severity of the disease [129]. Secretin
administration reduces the severity of cerulein-induced pancreatitis [130], a
fact that supports the protective effect of this ductal hypersecretion, although
this has been disputed [131,132]. The interplay between ductular and acinar
cells is also supported by studies demonstrating that pancreatic duct
obstruction alone can modify acinar cell membrane trafficking and the evolution
of pancreatitis [133]. This is possibly due to the increased intraductal
pressure, exposure of cells to bile acids, and acidification of the lumen
[134,135,136,137]. An increased intraductal pressure can activate the
mechanoreceptor PIEZO1 in the acinar cells to trigger the abnormal calcium
signaling discussed below [135] in concert with inflammation and activation of
the signal transducer and activator of transcription 3 (STAT3) pathway [138].
Acidification of the pancreatic lumen activates the transient receptor potential
vanilloid 1 (TRPV1) in the sensory neurons and causes acute pancreatitis [134].
PIEZO1-mediated and TRPV1-mediated mechanisms of AP are considered to be the
main underlying mechanisms for post-ERCP and gallstone pancreatitis [135,139].
Bile acids, on the other hand, can cause mitochondrial dysfunction and damage of
the ductal cells [126] that exposes acinar cells to high bile acid
concentrations, leading to their death [136,140,141].
These pathogenetic mechanisms are further analyzed.
3.1. CELLULAR MECHANISMS INVOLVED IN AP PATHOGENESIS
3.1.1. CA++ SIGNALING AND MITOCHONDRIAL DYSFUNCTION
Under normal conditions, Ca++ is released from the ER in association with
zymogen exocytosis and production of ATP in the mitochondria [142]. This is only
a transient increase in cytosolic Ca++, as two ATP-driven calcium channels
rapidly reduce the cytosolic calcium. The smooth ER Ca++ channels (SERCAs) send
Ca++ back into the ER, while the plasma membrane Ca++ channels (PMCAs) transport
Ca++ out of the cell [142]. Protracted elevation of Ca++ concentration in acinar
cells initiates activation of pro-inflammatory pathways, such as premature
trypsinogen activation, activation of the nuclear factor
kappa-light-chain-enhancer of activated B cells (NF-kB), and mitochondrial
dysfunction leading to cell death [143,144,145]. Alcohol and bile acids can
cause a sustained pathological cytosolic calcium elevation through the inositol
1,4,5-trisphosphate receptor (Ins (1,4,5) P3R) signaling pathway. Alcohol
metabolites in the acinar cells open Ins (1,4,5) P3Rs, which are Ca++ channels
located in the ER [146,147], thus increasing Ca++ release from the ER lumen
[145,148,149]. Increased Ca++ concentration activates the calcium channel
protein 1 (ORAI1) to further increase Ca entry into the cell from the outside,
maintaining the lethal cellular calcium concentration [150,151]. On the other
hand, ductal obstruction, as observed in post-ERCP and gallstone pancreatitis,
increases Ca++ entry from the outside through the mechanoreceptor PIEZO1, as
mentioned before [135]. Moreover, the high calcium concentration opens the
mitochondrial permeability transition pores (MPTP), abolishing the membrane
potential needed to generate ATP [145,152,153]. In turn, ATP depletion completes
a vicious circle, maintaining the high Ca++ concentration by disrupting the
ATP-dependent SERCAs and PMCAs’ clearance of excessive calcium. ATP depletion
also impairs other ATP-driven protective mechanisms, such as autophagy and the
UPR [122,142], promoting, therefore, acinar cell necrosis.
3.1.2. MITOCHONDRIAL DYSFUNCTION
Mitochondrial abnormalities of acinar cells are found in all forms and models of
pancreatitis. They cause reduction of ATP synthesis, increased ROS production,
and impairment of calcium transport [122,152,154,155,156]. In pancreatitis,
there is permeabilization of the mitochondrial membrane due to a sustained
opening of the MPTPs, the nonspecific channels crossing both IMM and OMM
[157,158,159]. Opening of the MPTPs allows for the uncontrolled entry of water
and solutes less than 1500 Da into the matrix, leading to inhibition of ATP
synthesis and cellular necrosis. On the other hand, inhibition of the MPTP
opening attenuates ATP depletion and acute experimental AP [152]. Not only
mitochondrial Ca++ overload, but also increased reactive oxygen species (ROS)
generation, cause MPTP opening. Peptidylprolyl isomerase D (cyclophilin D-CypD)
is an essential mitochondrial protein around which the MPTPs are organized. CypD
inhibition for any reason will block MPTPs’ opening and prevent AP [122,154].
Individual mitochondria form a network that is involved in the mitochondrial
activity [160]. In addition, abnormal mitochondrial membrane function releases
mitochondrial contents into cytosol, including cytochrome c, which lead to cell
death [161].
Aerobic metabolism in mitochondria generates most of the ATP, and only a small
quantity is produced by glycolysis. In pancreatitis, anaerobic conditions
predominate due to microvascular abnormalities and relative hypoxia of
pancreatic tissues. Therefore, the generation of ATP is reduced and not
sufficiently replaced by anaerobic glycolysis [30]. Acinar enzyme secretion and
ductular bicarbonate production are also significantly reduced [140,162,163]. It
should be noted that bile and fatty acids also inhibit ATP production from both
sources in acinar and ductal cells [140,164].
An additional difficulty in the pathophysiology of pancreatitis is that current
evidence indicates the formation of an interconnected system by different
organelles in the acinar cell. Damage of one organelle can lead to failure of
the entire network. Thus, the multiple organelle abnormalities found in acute
pancreatitis resemble the chicken and egg problem, as it is difficult to dissect
the different components responsible for the induction and evolution of AP
[122,165]. This is best exemplified in the involvement of the endoplasmic
reticulum in the pathophysiology of AP.
3.1.3. ENDOPLASMIC RETICULUM (ER) STRESS
Mitochondria and ER are closely associated with membrane domains [166,167]
providing the amount of calcium required for ATP generation [168,169].
Disruption of the ER–mitochondria interconnections leads to pathologic Ca++
signaling in the acinar cell and low ATP levels [168].
ER stress is the excessive accumulation of misfolded or unfolded proteins within
the ER lumen observed when the capacity of the ER to eliminate these proteins is
overwhelmed [170]. The pancreas is prone to ER stress because acinar cells
produce a large quantity of proteins daily, such as trypsinogen, lipase, and
several other lysosomal enzymes [171,172]. ER stress is found frequently in AP
and can be triggered by hypoxia, alcohol consumption, Ca++ overload, and
oxidative stress [173]. ER over-activation may be an important mechanism that
initiates and exacerbates pancreatic injury [174]. During ER stress, acinar
cells activate the UPR, which is a strictly controlled signaling pathway that
blocks protein translation and synthesis. Meanwhile, the UPR also increases
protein folding and the degradation of misfolded proteins, both of which relieve
ER stress. UPR uses three functional pathways, namely the inositol-requiring
enzyme 1 (IRE1), the activating transcription factor 6 (ATF6), and the protein
kinase RNA-like ER kinase (PERK) pathways [175,176,177]. The downstream signals
of the IRE1 and ATF6 pathways activate the transcription factors cATF6 and
spliced X-box binding protein 1 (sXBP1). These transcription factors increase
the synthesis of factors used for ER expansion and chaperones for protein
folding [178,179]. They also induce autophagy to recycle misfolded proteins
[180]. When UPR is overwhelmed, the apoptotic pathway is activated. On the other
hand, the PERK pathway is the terminal response, where its downstream
transcriptional factor CEBP homologous protein (CHOP) initiates apoptosis and
inflammation [177,181,182,183]. UPR also activates the NF-κB inflammatory
pathway, leading to exacerbation of acinar cell inflammation and cell necrosis.
Therefore, NF-kB inhibitors, such as IL-10, can block ER stress, reduce
pro-inflammatory cytokines, such as TNF-α, IL-1, and IL-6, and delay pancreatic
inflammation [184]. CHOP can also induce autophagy, but, in the end, it promotes
cell death during prolonged ER stress. Interestingly,
3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) inhibitors, which are used in clinical
practice, promote the UPR and may be used to prevent the recurrence of AP
[185,186].
3.1.4. TRYPSINOGEN ACTIVATION
Observations of pancreatic autolysis in postmortem studies made by the Austrian
pathologist Chiari in 1896 [187] formed the basis of the long-held
trypsin-centered theory of pancreatic injury.
Trypsinogen activation is the most widely studied pathogenetic mechanism of AP.
Premature trypsinogen activation is inhibited by the presence of trypsin
inhibitors and zymogen granule release [188]. Alcohol and bile acids stimulate
the synthesis of lysosomal digestive enzymes and inhibit the release of zymogen
granules at the apex of acinar cells. The lysosome and zymogen granules fuse
with one another in the so-called co-localization process [165,188]. Lysosomal
cathepsin B, in turn, activates trypsinogen, and both trypsin and cathepsin B
are liberated [189]. Cathepsin B release leads to necroptosis, a regulated form
of necrosis [190,191] that is mediated by the receptor-interacting protein
kinases 1-3 (RIP1-RIP3) and the mixed lineage kinase domain-like (MLKL) pathway
[192,193]. MLKL is phosphorylated and oligomerized by RIP3, and the oligomeres
are translocated into the plasma membrane, where they cause membrane puncture
and spillage of cellular contents [194]. Inhibition of the RIP1–RIP3 by the
inhibitor of RIP1 necrostatin attenuates acinar cell injury and can be used as
AP therapy [190,191,194]. Furthermore, GSK2982772, a novel RIP1 inhibitor,
represses necroptosis and inflammation [195,196] and may be tested in AP
treatment [194]. In addition, lysosomal membrane disruption activates caspase 3,
which initiates apoptosis through mitochondrial release of cytochrome c
[192,193].
Currently, premature trypsinogen activation in acinar cells is considered the
central mechanism in the pathogenesis of AP [197]. Recent findings, however,
indicate a more complex problem as trypsinogen activation was also observed in
macrophages [198,199], demanding further investigations. Macrophage activation
of trypsinogen induced translocation of NF-kB and the production of inflammatory
cytokines. Cathepsin B-knockout mice without trypsinogen activation in
macrophages developed less severe pancreatitis compared to controls
[198]. Moreover, another protease, cathepsin D, is expressed in pancreatic
acinar cells and macrophages regulating disease severity by activating cathepsin
B. Its effect is minimal in the early phase of pancreatitis and much greater in
the later, inflammatory cell phase of the disease [200]. These findings
challenge the long-held notion that premature trypsinogen activation occurs
exclusively within the acinar cells.
Finally, the strongest support for the trypsin-centered theory comes from the
identification of mutations in the trypsinogen gene PRSS1 in hereditary
pancreatitis, an uncommon form of pancreatitis with autosomal-dominant
inheritance [201].
Trypsin activation affects bicarbonate secretion in ductular cells as well. This
was attributed to the activation of the basolateral protease activated
receptor-2 (PAR-2) [202]. However, luminal administration of trypsin or PAR-2
activating peptide repressed bicarbonate production [203]. Similarly, the
severity of experimental pancreatitis can be either reduced or increased after
activation of PAR-2 [204,205,206]. Therefore, the matter requires further
investigation. Mechanisms of acinar cell injury are summarized in Figure 2.
Figure 2. Pathogenesis of acute pancreatitis. Black arrows: activation. Red
arrows: inhibition. ER: endoplasmic reticulum; MPTP: mitochondrial permeability
transition pores; ATP: adenosine triphosphate; CHOP: CEBP homologous protein;
DAMPS: damage associated molecular patterns; ETOH: Alcohol; SERCA: smooth ER
Ca++ channels; PMCA: plasma membrane Ca++ channels; UPR: unfolded protein
response.
ETOH and bile acid release cause acute pancreatitis through three mechanisms.
(1) They increase Ca++ release from the ER via the InsP3R pathway. Ca++ overload
increases the permeability of MPTP, leading to ATP depletion, which blocks SERCA
and PMCA and sustains Ca++ overload. Increased Ca++ overload activates
trypsinogen and inflammatory signaling pathways but also causes mitochondrial
dysfunction, leading to apoptosis and necrosis. (2) They inhibit the release of
zymogen granules, which fuse with lysosomes, leading to impaired autophagy.
Lysosomal cathepsin B causes premature trypsinogen activation and release of
cathepsin B and trypsin into the cytoplasm. The released cathepsin B acts on the
RIP3-RIP1-MLKL signaling pathway to promote RIP3-RIP1 necroptosis. It also leads
to the release of cytochrome-c from the mitochondria, which activates caspase-3
and cell apoptosis. (3) They trigger ER stress and UPR, leading to CHOP
expression and cell apoptosis. Necrotic or necroptotic cellular death liberate
DAMPS. For details, see text.
3.1.5. INFLAMMATION
Premature activation of digestive enzymes that occurs early in pancreatitis is
not sufficient to explain several aspects of AP. This is because the
inflammatory response in pancreatitis was reported to be independent of
trypsinogen activation [188]. Therefore, other mechanisms, such as NF-kB and
inflammasome activation, are now considered key pathogenic mechanisms in both
acute and chronic pancreatitis [30,207,208]. Findings in models of chronic
pancreatitis are quite interesting. The severity of fibrosis and the NF-kB
activation of chronic inflammation are not mitigated in cathepsin-B-deficient-
and trypsinogen-7-deficient mice, suggesting that inflammation is not dependent
on trypsin activation in both chronic pancreatitis and AP [209].
The NF-kB implication. Like in most inflammatory conditions, the activation of
NF-κB is an early event during pancreatitis observed within minutes after the
initiation of the disease due to the constitutive presence of N-FκB in the
cytoplasm of acinar cells before the initiation of AP [210,211]. Trypsinogen and
NF-κB activation are independent from each other, but they follow similar
kinetics [209], possibly due to their common activation by the intracellular
Ca++ signaling [212,213]. However, models of experimental pancreatitis suggest
an additional, complex involvement of NF-kB beyond the pro-inflammatory role. In
fact, data suggest that NF-kB may even protect acinar cells [214,215,216].
Moreover, mice overexpressing active IKKβ kinase showed chronic infiltration of
immune cells without acute pancreatitis, but administration of cerulein led to
more severe pancreatitis [217]. These findings indicate that constitutive
activation of NF-κB leads to an infiltration of immune cells, but pancreatitis
only develops after an additional external noxious stimulant.
Another important transcriptional component in acinar cells is AP1 (activator
protein 1). It controls pancreatic differentiation, cell death, and
inflammation. Mice heterozygous for the orphan nuclear receptor NR5A2 develop an
AP1-dependent pre-inflammatory state similar to early acute pancreatitis [218].
Interestingly, NF-kB and AP1 activity vary according to the etiology of
pancreatitis. In cerulein models, an activation of both factors was described
[219]. On the other hand, ethanol metabolites can either positively or
negatively regulate NF-kB and AP1 depending on the presence of oxidative or
non-oxidative alcohol metabolites in the pancreas [26,220]. Direct inhibition of
NF-kB by certain agents, such as the peroxisome proliferator activator receptor
gamma (PPAR-γ) ligand, pyrrolidine dithiocarbamate (PDTC), and calpain I
inhibitor, can ameliorate experimental AP, but the clinical significance is
still unknown [221].
The role of DAMPs. As a result of cell damage caused by injured acinar cells,
damage-related molecular patterns (DAMPs) can be released that may aggravate
pancreatic injury, leading to Systemic Inflammatory Response Syndrome (SIRS)
[222,223]. This stage of hyper-inflammation is followed by a compensatory
anti-inflammatory response syndrome (CARS), which is related to
immunosuppression and is characterized by an overproduction of anti-inflammatory
cytokines, such as TGF-β, IL-4, and IL-10 [224]. IL-10 inhibits the STAT3
pathway and the production of inflammatory cytokines [225]. The use of
insulin-like growth factor 1 and IL-4, which enhance IL-10 production, have
attenuated the damage in experimental AP [226,227]. However, it should be
stressed that during CARS, patients with acute pancreatitis are susceptible to
developing infection of pancreatic necrosis [228].
This idea was recently questioned, and a new approach was proposed where both
SIRS and CARS start early and develop in parallel, as shown in severe
pancreatitis induced by partial duct ligation with cerulein stimulation.
Pancreatic macrophages promote inflammation and simultaneously induce a
Th2-cell-mediated response via IL-18. The pro-inflammatory Th1 response was
scarcely detectable in concert with the absence of IL-12, a cytokine released by
M1-macrophage that regulates Th1 response. Regulatory T-cells were increased and
anti-inflammatory M2 macrophages were dominant, while M1-macrophages were
identified only in the necrotic areas. Inhibition of the NLRP3 inflammasome
reduced both SIRS and CARS. Interestingly, both pathways are regulated by the
NLRP3-inflammasome-derived IL-18 [229]. These findings, however, are not in
agreement with data from other cerulein models of AP [230] and patients with
severe acute pancreatitis [231], where IL-12 is detected and is a predictor of
disease severity. This discrepancy may be due to different mechanisms in
macrophage stimulation. In vitro activated macrophages after co-incubation with
acinar cells did not secrete IL-12, in contrast to macrophage activation with
LPS, which does induce IL-12 secretion [232].
DAMPs have a critical role in pancreatic inflammation. High mobility group box 1
(HMGB1) is a nuclear molecule constitutively expressed in almost every cell.
HMGB1 may translocate to the cytosol under stress, and then it is released into
the extracellular space where it functions as a DAMP with the ability to trigger
inflammatory mediators [233]. The circulating HMGB1 levels in AP are increased
and correlate with the severity of the disease both in humans and in
experimental animal models [234,235,236,237]. In addition, the inhibition of
HMGB1 protects from injury in models of AP [238,239,240,241,242]. In addition to
HMGGB1, damaged pancreatic acinar cells release different intracellular
contents, such as DNA, ATP, and heat shock protein 70 (HSP70), increasing NF-kB
activation through TLR4 activation. ATP released by damaged cells also interacts
with the purinergic receptor P2x7, inducing mitochondrial dysfunction. This is
followed by intracellular K+-depletion, which results in NLRP3 assembly,
caspase-1 activation, and IL1β and IL18 secretion [234]. Moreover, the
stimulation of intracellular nucleotide-binding oligomerization domain 1 (NOD1)
by translocated bacteria from the gut microbiota is a crucial element to
aggravate the inflammatory process in the pancreas.
The effects of DAMPs on macrophages were also investigated. Stimulator of
interferon genes (STING) activation in macrophages by DNA derived from damaged
acinar cells led to the overproduction of pro-inflammatory cytokines by
macrophages in experimental AP [243]. In the absence of STING, macrophages did
not overproduce cytokines, indicating a direct link between acinar cell DAMPs
and the generation of proinflammatory cytokines.
The role of inflammasome activation. Patients with AP have elevated serum levels
of pro-inflammatory cytokines, such as IL1β, TNFα, IL6, and IL18 [244]. The
precursor forms of IL1β and IL18 cytokines are converted into an active form
through the NLRP3 inflammasome. Two signals are required for the activation of
inflammasomes. The first signal upregulates the inflammasome mRNA by NF-kB and
the second signal initiates the activation of pro-caspase-1. The release of
cathepsins from phagosomes into the cytosol may act as the second signal in
inflammasome activation [245]. The NLRP3 inflammasome is activated during AP,
and its components are required for pancreatic injury. The absence of caspase-1,
caspase recruitment domain (ASC), or NLRP3 significantly reduced edema and
inflammation in AP [246]. Another study using NLRP3-deficient mice found
suppression of IL1β and prevention of the inflammatory cascade [247]. TLR4
involvement in the induction of AP has been reported. Administration of lactate
to block TLR4 reduced the activation of NLRP3 inflammasome [248]. This finding
agrees with clinical data showing an anti-inflammatory effect of Ringer’s
lactate solution used as a fluid replacement in patients with AP [249,250].
Other TLR4 modulators, such as carbon monoxide, produced similar results,
indicating a clear role of TLR4 and the NLRP3 inflammasome in AP [251,252]. The
NLRP3 inflammasome is also implicated in the development of lung injury
secondary to pancreatitis through exosomal release. The plasma-derived exosomes
trigger NLRP3 inflammasome activation and pyroptosis in alveolar macrophages,
leading to ppulmmonary dysfunction during AP [253]. A human study confirmed
animal data. The report confirmed the presence of increased levels of AIM2 and
NLRP3 inflammasomes in the early course of AP. Furthermore, AIM2 expression was
increased in patients who developed moderate or severe AP [254].
Other factors connecting acinar cell damage and inflammation have been
described. Histone deacetylase (HDAC) is one of these factors, as HDAC activity
has been demonstrated to play a crucial role in the regulation of inflammation
in AP. HDAC inhibition reduced trypsinogen activation, inflammation, and tissue
damage in experimental AP [255]. Additionally, inhibition of Sulfiredoxin-1
(Srxn1) expression was reported to increase the production of ROS and induction
of apoptosis. Inhibition also promoted inflammation by accumulating M1
macrophages and neutrophils in AP. Overexpression of Srxn1 reduced ROS and
apoptosis in acinar cells [256].
Details of inflammatory mechanisms in AP have been published [29].
3.1.6. ROLE OF THE IMMUNE SYSTEM
Early in the course of AP, the pancreas is infiltrated by inflammatory cells.
Macrophages and neutrophils are the first to reach the organ and contribute to
the pancreatic damage phagocytosing necrotic tissue [257]. Pancreatitis is a
sterile inflammation, and pathogen-associated molecular patterns (PAMPs) play no
role, at least in the early phases. The activation of immune cells is mediated
by damage-associated molecular patterns (DAMPs) that arise from acinar cell
necrosis. DAMPs increase the nuclear translocation of the NF-kB family within
infiltrating immune cells, leading to enhancement of the cytokine storm [198].
Injured acinar cells also release chemokines that recruit immune cells within
minutes after the onset of disease into the site of injury [221,258] The
monocyte chemoattractant protein 1 (MCP1) facilitates monocyte trafficking,
while macrophage inflammatory protein 2α (MIP2α) and CXC chemokine ligand 1
(CXCL1) recruit macrophages and neutrophils [259,260]. Inhibition of chemokines
and their receptors prevents pancreatic and distant organ injury in animal
models [261,262,263]. Increased serum MCP1 levels correlate with severe acute
pancreatitis in humans [264]. Neutrophilic NADP oxidase promoted oxidative
stress and increased intra-acinar trypsinogen activation [265,266]. The
infiltration of immune cells has been also associated with the prognosis of
pancreatitis [267,268,269]. Macrophage infiltration better correlates with
pancreatic damage and necrosis than the number of neutrophils because
macrophages are required for the removal of necrosis and thus ameliorate
pancreatic damage. Phagocytosing macrophages are found in almost all models of
AP and CP [198,267,270,271]. Depletion of macrophages decreases disease severity
and protects mice from cerulein-induced pancreatitis [263,267]. Macrophages also
produce large amounts of IL1β, which is released by the gasdermin D pore complex
from the cytosol into the extracellular space. Consequently, the cell undergoes
pyroptotic cell death [272,273,274]. Macrophages at distant organs are also
activated and contribute to distant organ damage in AP, although the mechanisms
of distal organ injury have not been fully elucidated [264].
The role of neutrophil extracellular traps (NETs). Activated neutrophils use
nuclear DNA and histones to form extracellular web-like structures called
neutrophil extracellular traps (NETs) that participate in microorganism
eradication. However, NETs can cause ductal obstruction, activate
pro-inflammatory signals, and prematurely activate trypsinogen [275]. During
experimental AP, NETs are produced in the pancreas, regulating organ
inflammation and injury. NET levels are also increased in plasma from patients
with AP [150,276].
NETs act as a double-edged sword, regulating, on the one hand, the protective
innate immune response, but also precipitating in epithelial and tissue injury
[277,278]. NETs are also associated with the severity of AP [279]. In septic AP,
NETs kill invading pathogens [275] but also activate trypsinogen, mostly through
the STAT-3 pathway [280]. NETs may also cause severe damage to other organs,
such as the lungs, blood vessels, and kidneys [281,282]. NETs are implicated in
thrombosis and participate, therefore, in the hypercoagulability observed in the
incipient stage of severe acute pancreatitis [280]. Additionally, NET formation
increases macrophage recruitment by releasing chemokines.
As a consequence of these abnormalities in immune mechanisms, a paradoxical
period of immunosuppression develops during AP. In patients with mild and
moderate AP, there is a reduction in HLA-DR expression within the first few days
of the disease, but this returns to near-normal levels within the first week
[283]. In contrast, in patients with severe AP, the reduction of HLA-DR
expression persists for a long period, and these patients may develop infectious
complications [284]. A recent study reported increased activity of the PD1/PD-L1
system in severe pancreatitis, which was more pronounced in patients who develop
secondary infectious complications [285]. Another serious consequence of the
abnormal immune mechanisms in AP is the impairment of the intestinal barrier,
leading to systemic bacterial translocation. In most AP patients, gut barrier
failure occurs at the point of hospital admission [286], before the onset of
multi-organ failure. Increased intestinal permeability has been observed even in
mild disease, although it is more pronounced in severe disease [286,287,288],
when patients are more vulnerable to infections [289]. A review of
immunopathological abnormalities in AP has very recently been published [289].
Taken together, early protease activation as well as NF-κB and inflammasome
activation are essential mechanisms of pancreatitis. These events occur in
parallel during disease evolution and strongly influence each other. Recently,
it has become clear that not only the activation of proteases and NF-κB play a
critical role, but also the type of cell where these events take place.
Pancreatitis is no longer a disease of acinar cells alone [26]. The role of
inflammation and immunity is summarized in Figure 3.
Figure 3. Inflammation in acute and chronic pancreatitis. Black arrows:
activation. For more details, see text. LPS: lipopolysaccharide; HSP70: heat
shock protein 70; HMGB1: high mobility group box 1; TLR4,9: toll like receptor
4,9; ROS: reactive oxygen species; ATP: adenosine triphosphate; NETS: neutrophil
extracellular traps; NLRP3: NLR pyrin domain containing protein 3; ASC: caspase
recruitment domain; NOD1: nucleotide-binding oligomerization domain 1; MCP1:
monocyte chemoattractant protein 1; mtDNA: mitochondrial DNA; PSC: Pancreatic
stellate cells; MIP2: Macrophage inflammatory protein-2.
DAMPs, such as HMGB1, HSP70, and ATP, are crucial for the promotion of acute
pancreatitis and, indirectly, of chronic pancreatitis. They activate NF-kB
through TLR4 and upregulate the mRNA and protein expression of NLRP3, leading to
the assembly of the NLPR3 inflammasome in association with ASC and
pro-caspase-1. In addition, bacterial translocation sustains inflammation
through the NOD1. NLRP3 and casp-1 are activated by either ATP via its
interaction with P2X7 and the resultant intracellular K+-depletion or the ROS
produced by NETs. Maturation of pro-IL1β and pro-IL18 leads to IL1β and IL18
secretion and inflammation. Some intracellular DAMPS, such as mitochondrial DNA,
initiate NLRP3 inflammasome assembly and activation. Additionally, TLR9 senses
intracellular bacteria and mtDNA with subsequent activation of NF-κB. Chemokines
produced by injured acinar cells recruit and activate macrophages and
neutrophils at the site of injury. Cytokines, such as TGFβ1, produced by
macrophages activate PSCs to produce extracellular matrix initiating fibrosis in
chronic pancreatitis. Neutrophils also release NETs, aggravating inflammation.
3.1.7. EXOSOMES AND AP
Exosomes are vesicles secreted by various living cells that contain RNA and
proteins (30–100 nm in size). In experimental pancreatitis, the number and
content of the exosomes released to the peripheral blood from the pancreas are
significantly increased. As mentioned before, pancreatic exosomes can reach the
lung through circulation, where they are phagocytosed by alveolar macrophages,
changing their phenotype from M2 to M1, which in turn aggravates the lung injury
caused by AP [290]. Plasma-derived exosomes may activate lung NLRP3
inflammasomes to induce pyroptosis of alveolar macrophages in AP. Inhibition of
these exosomes represses the pyroptosis of alveolar macrophages, attenuating the
AP-induced lung damage [253]. The interplay between acinar cells and macrophages
has been confirmed through analysis of microRNAs found in exosomes. Acinar cells
activate macrophages through exosomes released in AP, which in turn promote
acinar cell injury via apoptosis, necrosis, and autophagy [291]. Exosomes
derived from different cells are not always detrimental in AP. Thus, exosomes
derived from bone marrow mesenchymal stem cells (MSCs) have a protective effect
on AP [292]. The specificity of exosomes in different cells and tissues should
be further investigated [125].
3.1.8. GENETIC MUTATIONS
Several gene mutations are implicated in the pathogenesis of acute pancreatitis,
such as mutations in protease serine 1, serine protease inhibitor Kazal type 1,
chymotrypsin C, the cystic fibrosis transmembrane conductance regulator (CFTR),
claudin 2, and calcium-sensing receptor genes [293]. Human genetic data indicate
that premature activation or misfolding of pancreatic proteases play a central
role in the onset of pancreatitis and progression to chronic pancreatitis [26].
A detailed presentation of these genetic mutations is beyond the scope of this
review, but a paper is available that elegantly summarizes the genetics of acute
pancreatitis [294].
4. CHRONIC PANCREATITIS
4.1. PATHOPHYSIOLOGY OF CHRONIC PANCREATITIS (CP)
Multiple mechanisms are involved in the pathogenesis of CP. Repeated insults to
the pancreas by alcohol or tobacco or any other factor may lead to recurrent
attacks of AP, which in turn activate pancreatic stellate cells (PSCs) and
initiate fibrogenesis, ultimately resulting in chronic fibrosing pancreatitis.
Interestingly, these recurrent attacks very frequently cause histopathological
abnormalities in the pancreas in many patients, who remain asymptomatic, and
only a few experience clinical disease [31,295,296,297]. After repeated
episodes, areas of pancreatic necrosis are replaced by fibrotic tissue
[298,299]. However, pancreatic necrosis is uncommon in patients with classic
chronic pancreatitis.
Another theory is the “two-hit” model. After infiltration of the pancreas by
macrophages and neutrophils during an episode of AP and the activation of
pancreatic stellate cells (PSCs), a second continuous insult, such as alcohol
and tobacco and their metabolites, will promote fibrosis through activated
immune cells [300,301,302,303]. However, most patients do not proceed to CP
despite continuous use of these toxic factors. Earlier reports pointed to the
role of ROS production by acinar cells and the subsequent activation of NF-kB
[267]. ROS can promote the fusion of lysosomes and zymogen granules and the
premature activation of trypsinogen [304,305]. This theory totally ignores the
critical role of ROS production by macrophages. Finally, a ductal dysfunction
has been connected to CP pathogenesis. Reduction of secretion of
bicarbonate-rich fluid [306] favors the formation of protein plugs and ductal
obstruction. Protein plugs are indeed described in chronic pancreatitis [298],
but it is not clear if they are the cause or the result of CP.
The drawbacks of all of the theories presented above indicate that external
factors are not sufficient to explain the development of CP. Whatever the
pathogenesis of CP might be, its development leads to pancreatic exocrine
insufficiency, diabetes mellitus, and an immune response that results in nerve
abnormalities and chronic pain [307,308].
Mutations in several genes, such as the cationic and ionic trypsinogen or the
pancreas-specific protease elastase 3b (CELA3B), have been implicated in the
pathophysiology of CP to complete some of the missing points [16,26,309,310].
Therefore, it seems that a different “two-hit” model, where the first step is an
underlying mutation and the second is the effect of toxic external factors, is a
more comprehensive pathogenetic theory. The influence of external risk factors
is very strong. In patients with CP, the pooled prevalence of alcohol as a risk
factor is 65% compared to the risk factor of 61% of tobacco [17]. Smoking or
alcohol abstinence reduces the risk of disease progression [311,312]. Alcohol
toxicity is due to its metabolites [313,314] that cause the microcirculatory
disturbances, which in turn mediate pancreatic acinar cell injury, resulting in
fibrosis and chronic disease [172,315]. Recently, macrophages and pancreatic
stellate cells are in the center of extensive investigation to clarify their
role in the pathogenesis of CP [316].
4.2. THE ROLE OF MACROPHAGES
Macrophages are the main inflammatory cells implicated in CP fibrosis [317].
Fibrogenesis in CP is induced when macrophages and other inflammatory cells are
attracted by tissue damage and infiltrate the pancreas [318]. Necrosis and
apoptosis of acinar cells can activate macrophages. Macrophages produce
transforming growth factor-β1 (TGF-β1), platelet-derived growth factor (PDGF),
and connective tissue growth factor (CTGF), which initiate activation and
proliferation of the resident PSCs, which are transformed in mmyofibroblast-like
cells (PMF) [319,320]. Activated macrophages create a positive feedback cycle
through PSCs to secrete more cytokines [198,321]. Activated PSCs in turn induce
M2 macrophages that play a significant role in angiogenesis and promote tissue
fibrosis [322,323,324,325].
4.3. THE ROLE OF PSCS
PSCs are able to oxidize alcohol to acetaldehyde, leading to the generation of
ROS and oxidative stress. As mentioned before, alcohol consumption damages the
intestinal barrier and increases circulating levels of lipopolysaccharide,
oxidized low-density lipoproteins, and TNF-α. All of them are potential
activators of PSC in concert with TGF-β1 [326,327]. The resultant myofibroblasts
secrete increased amounts of extracellular matrix proteins, thus mediating
pancreatic fibrosis [328,329,330]. Mice overexpressing TGF-β1 develop
spontaneous pancreatic fibrosis, indicating that TGF-β1 activates de novo PSCs
[331]. Activated PSCs can also secrete CTGF, IL-1/16, and endothelin-1 (ET-1)
and further promote the activation of PSCs through autocrine and paracrine
signaling, which forms a vicious cycle [332]. At present, TGF-β is the strongest
activator of PSCs. This effect is achieved by regulating the Smad2/3 signaling
pathway [333,334]. This mechanism also influences the phosphorylation of three
subtypes of the MAPK family, including c-Jun amino-terminal kinase (JNK), p38,
and ERK [335,336,337]. All of these signals work in parallel, leading to
pancreatic fibrosis [338,339,340]. While TGF-β1 is critical for promoting matrix
deposition by myofibroblasts, it fails to induce PMF proliferation, in contrast
to PDGF, wwwwhich drove proliferation of PMFs isolated from CP patients [341].
PDGF also stimulated the production of a matrix with reduced potency compared
with TGF-β1 [342]. PDGF itself is not capable of initial activation of PSCs
[343].
CTGF is the third activator of PSCs. In CP specimens, CTGF and TGF-β1 were
increased more than 20-fold [344]. It should be noted that CTGF expression in
the pancreas is controlled by several cytokines, such as TGF-β1, Activin-A,
PDGF, and TNF-α [345,346].
Additional external activators of PSCs are TNF-α, IL-1β, and Cyclooxygenase-2
(COX2). Incubation of PMFs with TNF-α increased α-SMA expression [342,347,348].
The COX2 downstream product Prostaglandin E2 stimulated PMF proliferation and
the expression of matrix proteins and matrix metalloproteinases [349]. In a
different model, ectopic expression of COX-2 in the acinar cells of rodents led
to spontaneous CP, with deposition of ECM proteins [350]. PMFs are also
sensitive to DAMPs. Rodent PMFs express TLRs 2, 3, 4, and 5, along with
co-receptors CD14 and MD2 [351]. TLR2 and 4 are known receptors of high mobility
group box 1 (HMGB1), heat shock protein 70 (HSP70), and fibrinogen, indicating
that DAMPS are directly implicated in pancreatic fibrosis. In addition to DAMPs,
acinar cell damage can directly activate PSCs. After trypsinogen activation,
acinar cells liberate a large number of cytokines that activate PSCs and induce
fibrosis [352,353,354]. Acinar cells in CP gradually change from columnar to
flat and form a ductal structure expressing cytokeratin. This transformation is
called acinar ductal metaplasia (ADM), and it is a promoter of fibrosis and an
early event of pancreatic adenocarcinoma [355,356].
Two more factors that activate PCSs prove the complex nature of fibrosis
development in CP. Hypoxia activates PSCs with the increased release of type I
collagen, fibronectin, and vascular endothelial growth factor (VEGF) [357]. As
mentioned before, high pressure in the pancreatic duct stimulates Piezo1 channel
opening, leading to PCSs’ activation and pressure-induced chronic pancreatitis.
This mechanism may explain the fibrosis developed in biliary CP [358]. Details
of the activation of PSCs were recently published [359,360].
In addition to the innate response mostly mediated by macrophages, several
studies have demonstrated an involvement of adaptive immunity as well [361].
Increased clusters of CD4+ and CD8+ T cells in parallel with increased IL-10
levels have been reported in CP patients compared with healthy individuals
[362]. Moreover, chronic pancreatitis specimens had more disease-specific
regulatory T-cell subsets [363] and central chemokine receptor 7 (CCR7) positive
memory T cells that persisted up to 3 years after pancreatic resection [364].
5. A BRIEF SYNOPSIS OF FORMS OF CELLULAR DEATH IN ACUTE AND CHRONIC PANCREATITIS
1.
Apoptosis was the first form of regulated cell death (RCD) to be described
[365]. Apoptosis includes both external and internal pathways. The external
pathway is initiated by death receptors (such as TNF receptors or Fas receptors)
and mediated by the initiator caspase-8. Intrinsic apoptosis is initiated by
MOMP, which leads to the release of mitochondrial proteins, such as cytochrome
c, and diablo IAP-binding mitochondrial protein (DIABLO, also known as Smac),
and subsequent activation of the initiator caspase-9 [366]. Both pathways lead
to the activation of executionar caspases and cellular death.
2.
Necroptosis. The regulated process of necrosis is called necroptosis. It is
mediated by RIPs and MLKL, as mentioned before. Compared to apoptosis,
necroptosis may be a more aggressive mode of cell death. Recent studies
indicated that necroptosis may be the main mechanism of acinar cell death in AP
[365,367,368].
3.
Pyroptosis is the result of NLRP3 and other inflammasome activation. IL-37
protects against acinar cell pyroptosis in AP [369]. The activation of
pyroptosis includes the caspase-1-dependent canonical pathway and the
caspase-4/5/11-dependent non-canonical pathway. Caspases-3-7-8, implicated in
apoptosis, also participate in the regulation of pyroptosis [370].
Caspases-1-4-5-11 directly cleave the gasdermin D (GSDMD) to produce N-terminal
fragments. GSDMD forms pores in the plasma membrane, followed by membrane
rupture. It has been proposed that a shift from apoptosis to pyroptosis and
necroptosis may explain why some patients with pancreatitis develop the
necrotizing form of the disease [229,371].
4.
Ferroptosis is a new RCD pathway that is an iron-dependent form of non-apoptotic
cell death first described in 2012. It is induced by accumulation of peroxidized
lipids and is regulated by glutathione peroxidase 4 (GPX4) and arachidonic acid
lipid oxygenases [372]. Ferroptosis plays an important role in the death of
acinar cells, at least in AP, associated with hypertriglyceridemia. NADPH
oxidase 2 (NOX2) is a key point in the regulation of ferroptosis. The inhibition
of ferroptosis and NOX2 attenuated the inflammatory response in a rodent model
of AP and improved the outcome [373].
6. AUTOPHAGY IN PANCREATITIS
Autophagy is the cellular pathway for organelle, lipid, and protein degradation.
It is the more efficient recycling machinery in nature [96].
Genetic models targeting autophagy have in part clarified the significant role
of this system in the pancreatic pathophysiology. The role of autophagy was
investigated in mice with pancreas-specific knockouts of mediators of
autophagosome formation, the autophagy-related proteins ATG5 or ATG7. Genetic
deletions of ATG5 or ATG7 or of the inhibitor of nuclear factor IκB kinase α
(IKKα) result in ER stress and accumulation of dysfunctional mitochondria unable
to generate ATP [178,271]. Moreover, the lysosome associated membrane protein 2
(LAMP2) deficiency increased the severity of cerulein pancreatitis [270,374].
Administration of the enhancer of autophagy trehalose significantly reduced
trypsinogen activation and necrosis in a murine pancreatitis model [122].
Importantly, tissue from patients with pancreatitis showed abnormalities of
autophagy similar to those in murine models [122,374,375,376]. These will be
analyzed below. The AP models of IL-22 transgenic mice are a further indication
of autophagy involvement in AP, as IL-22 can prevent the formation of
autophagosomes through the Beclin-1 pathway, reducing the severity of AP [377].
An important aspect of autophagy in severe AP is the effect of autophagy on the
integrity of intestinal barrier. Reduced autophagy in severe AP impairs tight
and gap junctions and reduces the function of goblet and Paneth cells, leading
to increased bacterial translocation and extra-pancreatic serious manifestations
[370,378,379]. The increase in oxidative stress associated with the increased
bacterial translocation will aggravate AP-associated lung injury and was
attributed to decreased autophagy levels [380]. However, the opposite has also
been reported, as excessive autophagy may also be connected to lung injury. It
was recently shown that the nuclear translocation of Nrf2 reduced excessive
autophagy in severe acute pancreatitis-related acute lung injury via the
p62–Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2)
signaling pathway in mice [381].
Recent investigations have revealed more associations of autophagy and
pancreatitis. Thus, an additional connection between zymogen exocytosis and
autophagy has been reported involving SNARE proteins. Syntaxin 2 (STX-2), a
SNARE protein of the acinar cell, blocked the fusion of zymogen granules with
the plasma membrane and exocytosis and, at the same time, deregulated
autophagosome formation by disrupting autophagy-related 16-like 1 protein
(Atg16L1), an interaction with the clathrin heavy chain. This interaction is
necessary to recruit membranes from acinar plasma membrane for physiologic
autophagosome formation [382]. Notably, depletion of another SNARE protein,
SNAP23, prevented the induction of AP by reducing trypsin activation of
autolysosomes [383].
Xanthohumol (Xn), a natural prenylated chalcone compound isolated from hops,
restored autophagy flux by inhibiting the AKT/mTOR pathway in experimental
pancreatitis. This was associated with reductions in necrosis, inflammation,
oxidative stress, and the severity of pancreatitis [384]. Experiments also
indicated that Pancreatic Protein kinase C iota (PKCi) significantly increased
pancreatic immune cell infiltration, acinar cell DNA damage, and apoptosis, but
reduced sensitivity to cerulein-induced pancreatitis. Prkci deletion in acinar
cells resulted in p62 aggregation and loss of autophagic vesicles consistent
with the disruption of autophagy [385].
Farnesoid X receptor (FXR) has been also implicated in pancreatitis. FXR is a
ligand-activated factor that has an important role in the regulation of glucose,
lipid, bile acid, and amino acid metabolism [386]. FXR is also an
anti-inflammatory factor in several inflammatory diseases [387,388]. Nuclear FXR
was considerably increased in the pancreas of patients with pancreatitis
accompanied by a parallel increase in Oxidative Stress Induced Growth Inhibitor
1 (OSGIN1), which is the direct target of FXR in the exocrine pancreas. Deletion
of the FXR in acinar cells caused severe pancreatitis, whereas pancreatic
overexpression of Osgin1 reduced the severity of pancreatitis. Stimulation of
autophagic flux by the FXR-OSGIN1 axis was the mechanism through which
FXR-OSGIN1 protected against pancreatitis [389].
A selective autophagic pathway called zymophagy is an early protective mechanism
in AP preventing acinar cell death [390,391]. It may be induced by CCK-receptor
hyperstimulation and may account for the self-limited form of AP [390].
The protective effect of canonical autophagy was reported in a recent study
comparing canonical autophagy with the Ras-related protein Rab9-mediated
non-canonical autophagy, which was not protective. These two forms of autophagy
antagonize each other. Thus, Rab9 decrease as observed in rodent and human
pancreatitis may be a beneficial response to boost canonical autophagy and
mitigate disease severity [392].
Autophagy and autolysosomes are additionally involved in trypsinogen activation,
as suggested by earlier reports. In a model of AP with atg5 deletion, reduced
severity of the disease paralleled reduced trypsinogen activation [393,394], a
finding verified by a subsequent study [376]. Trypsinogen activation and the
role of autophagy have been reviewed in detail [395,396].
6.1. AUTOPHAGY AND ER IN AP
ER is responsible for the synthesis and folding of proteins, the storage of
Ca++, and the regulation of Ca2+ concentration in cells [397]. Endoplasmic
reticulum stress (ER stress) develops when the ER is overwhelmed by unfolded and
misfolded proteins. Morphological changes in ER indicating ER stress, such as
swollen ER, vacuolation, and loss of ribosomes, are observed at the early stage
of AP [398,399]. ER is closely associated with autophagy. The major membrane
source for the creation of autophagosomes is the rough endoplasmic reticulum,
and both the initiation and maturation of autophagosomes have a close
relationship with ER [179,400,401]. Autophagy will be interrupted, or the
already impaired autophagy will deteriorate after the development of ER stress.
Moreover, IL-1β released by macrophages can cause ER stress and liberation of
large amounts of Ca2+ from ER into the cytoplasm, leading to both activation of
trypsinogen and impaired autophagy in murine pancreatitis [402,403,404]. Alcohol
consumption can also induce ER stress that impairs lysosomal proteases and
lysosomal membrane proteins, such as LAMP2, leading to deranged autophagy and
initiation of AP [405]. The deletion of IκB kinase α (IKKα) gene impaired
autophagy and P62 accumulation, leading to ER stress and spontaneous
pancreatitis [375]. With P62 gene deletion, all of these damages were mitigated,
suggesting that autophagy impairment can indeed cause ER stress [176,406]. The
ATG7 gene knockout model showed that autophagosomes are not formed in acinar
cells, and autophagy flux is reduced while ER stress is increased [178].
Trehalose, which can increase autophagy activity and restore autophagy flux,
reduces ER stress and trypsinogen activation, thus alleviating AP, as mentioned
before [122]. In a different murine, it was also shown that reduction of
autophagy aggravated AP and increased ER stress [407]. Taken together, these
findings indicate that there is a reverse association between autophagy and ER
stress. This is further confirmed by evidence suggesting that restoration of ER
function could in turn promote autophagy and protect acinar cells. Thus,
melatonin administration inhibited the EER stress and promoted autophagy,
alleviating AP [408]. Finally, it should be noted that there is a synergy
between UPR and autophagic pathways. Both UPR and autophagy aim to restore ER
function, as autophagy also degrades misfolded proteins, and the specialized
form of reticulophagy removes damaged ER [405,409].
6.2. AUTOPHAGY AND MITOCHONDRIA IN AP
Mitochondrial dysfunction can lead to impairment of autophagy through the
CypD-related MPTP opening. In some AP animal models, such as the cerulean and
bile acid models, mitochondrial dysfunction in acinar cells is moderated through
Ca2++-dependent pathways [161]. Ca2++-independent pathways may operate in other
models, such as the Arginine-induced model of AP, where the opening of MPTPs is
due to the decreased ATP synthase activity [410], while the MPTP opening in
alcoholic AP is mediated by the reduction of Nicotinamide adenine dinucleotide
(NAD) [354]. Finally, they all lead to continuous opening of the MPTPs, which is
controlled by the mitochondria resident protein CypD [122,152]. Inactivation of
CypD restores mitochondrial polarity and ATP synthase activity, proving that
mitochondria regulate lysosomes and therefore autophagy in the pancreas
[122,152,155]. In more detail, in the arginine model, free Arg in the
mitochondria of acinar cells increased, and it was degraded through the
ornithine pathway. The degradation product reduced ATP synthase, resulting in
reduced autophagy, ER stress, and lipid metabolism disorders, ultimately leading
to AP [122]. It was recently reported that loss of estrogen-related receptor γ
(ERRγ) resulted in mitochondrial dysfunction and further increased autophagosome
accumulation and ER stress in acinar cells [411].
In addition, impaired autophagy can also influence mitochondrial function
through inefficient mitophagy, the selective autophagy of mitochondria [84,154].
Acinar cell survival depends on the efficient removal of damaged mitochondria.
AP in mice induces mitophagy by up-regulating Parkin, an E3 ubiquitin-protein
ligase that initiates mitophagy, as mentioned before [179,412]. Normal mitophagy
may in part explain the mild course of AP in the majority of patients. However,
the deletions of atg5 and atg7 genes inhibit mitophagy and lead to the
accumulation of dysfunctional mitochondria [178,271], suggesting that the
impaired autophagy observed in AP is finally accompanied by reduced mitophagy
[354]. Recently, a new pathway for mitophagy was demonstrated in AP. Alterations
of mitochondrial dynamics and subsequent mitochondrial dysfunction were shown
early in the acute phase of mild pancreatitis. Moreover, it was shown that the
vacuole membrane protein-1 (VMP1) is necessary in mitophagy, as VMP1
downregulation significantly reduced mitochondrial degradation [413].
Overproduction of ROS may also disrupt mitophagy, causing severe AP by
activating the AKT/mTOR pathway [414]. So far, the results in human AP agree
with the experimental findings.
6.3. AUTOPHAGY AND LYSOSOMES IN AP
The lysosome contains more than 60 acid hydrolases. It is protected from
auto-ddegrradation by a glycocalyx of the membrane [415,416]. The lysosome is
considered today to be an important coordinator of signals regulating cell
growth, proliferation, and differentiation, in addition to its participation in
the final stage of autophagy [417]. Cathepsins are the most important acid
hydrolases of the lysosomes [418]. Dysfunction of the lysosomes can block
autophagy through three mechanisms. The first mechanism is the impairment of the
fusion of lysosomes with autophagosomes due to the defective function of the
lysosomal membrane proteins, LAMP-1 and LAMP-2 [270,419,420]. This is an
important mechanism of alcohol’s induction of AP and CP. In murine pancreatitis,
alcohol reduces LAMP-2 proteins, leading to the accumulation of autophagosomes
in acinar cells and a shift from apoptosis to necrosis [374]. Patients with
alcoholic pancreatitis also have local LAMP-2 depletion. Abnormal cathepsins are
the basis of the second mechanism. Pancreatitis impairs the maturation of
cathepsins in lysosomes of acinar cells, resulting in the accumulation of
autolysosomes with undegraded material, including zymogen granules [395]. It
should be noted that a reduction in enzymatic activities of cathepsins in
pancreatic lysosomes has been reported in AP [421]. An imbalance between
cathepsin L and cathepsin B may be the underlying reason. As mentioned before,
cathepsin B converts trypsinogen to trypsin, while cathepsin L degrades both
trypsinogen and trypsin. Inhibition of cathepsin L may therefore lead to
increased activity of trypsin and pancreatitis [376]. Inadequate synthesis of
lysosomes leading to autophagy reduction and induction of AP is the third
mechanism. Transcription factor EB (TFEB) is the central regulator of lysosome
synthesis [70] and also a transcriptional factor of several autophagy-related
genes [422,423]. TFEB is degraded in the cerulein model of AP, resulting in
autophagy impairment [424]. Deletion of tfeb increased the severity of murine
AP, while tfeb overexpression attenuated pancreatitis [425]. It should be noted
that defective or aging lysosomes are phagocytosed by autophagosomes and fused
with normal lysosomes for degradation through a process called lysophagy
[426,427].
Recently, the importance of normal cathepsins was demonstrated in a
double-knockout (DKO) model of cathepsin deficiencies. Cathepsin B/cathepsin D
DKO mice showed cytoplasmic degeneration similar to atg5 KO mice. The autophagy
markers LC3 and p62 accumulated, and the numbers of autophagosomes increased in
the acinar cells. Moreover, these mice developed CP, indicating the significance
not only of cathepsin B but also the significance of the combination with
cathepsin D. Single KO mice for either cathepsin were normal [428].
6.4. THE ROLE OF MIRNAS IN REGULATING AUTOPHAGY OF AP
As mentioned above, there is an interplay between different organelles and
autophagy in pancreatic acinar cells. Several microRNAs are involved in this
interplay. Thus, miR155, miR141, miR-181b, miR-148a, and miR-375 contribute to
the inhibition of autophagy initiation by inhibiting the expression of Beclin-1.
The repressed expression of ATG12 and p62 and the downregulation of LAMP-2 by
miR-148b-3p will also derange autophagy [429].
On the other hand, MiR-92b-3p was reported to attenuate inflammation and
autophagy in cells incubated with cerulein by targeting tumor necrosis factor
receptor-associated factor-3 (TRAF3) and repressing the p38 pathway [430]. An
additional regulation of autophagy by miRNAs is via the
calcium/calmodulin-dependent protein kinase II (CAMKII). It mediates the
phosphorylation of its substrates in response to cytoplasmic Ca++ increase
[431,432]. In addition, CAMKII is auto-phosphorylated after the entry of Ca++
into acinar cells and acquires Ca++-independent activity [433]. CAMKII activity
is necessary in one model of AP induced by nicardipine [432]. Pancreatic
necrosis parallels the level of CAMKII, which is positively controlled by ATG7,
suggesting that there is a connection between impaired autophagy and
CAMKII-regulated necrosis in the pathogenesis of AP. The level of miR-30b-5p was
negatively correlated with the levels of ATG7, indicating that the
well-described impairment of autophagy is associated with low ATG7 and the
subsequent necrosis of AP is mediated by the miR-30b-5p/CAMKII pathway [434].
6.5. INTERPLAY OF AUTOPHAGY AND INFLAMMATORY RESPONSE IN PANCREATITIS
Autophagy elimination through deletion of the genes atg5, atg7, lamp-2, or ikkα
increases the inflammatory reaction associated with up-regulated production of
cytokines, chemokines, and macrophage infiltration of the pancreas, as mentioned
before [178,270,271,375]. Both inflammatory (M1) and fibrogenic (M2) macrophages
are increased. M1 macrophages predominate in LAMP2-null mice with cerulein
pancreatitis, while neutrophils are decreased, indicating a shift towards
chronic inflammation [270]. In ATG5-deficient mice, autophagy blockade activates
NF-kB, STAT3, and cJun N-terminal kkinases, all of which stimulate production of
cytokines by acinar cells [435]. ATG5 deficiency also activates the IκB kinase
(IKK)-related kinase (TBK1) and increases the infiltration by neutrophils and
T-cells accompanied by PD-L1 upregulation, increased levels of type I interferon
(IFN), and the IFN-regulated chemokine CCL5 [436]. As mentioned before,
persistent ER stress is observed in mouse models of AP [437] and CP [438].
Autophagy suppression is one of the inducers of ER stress in experimental
pancreatitis [178,271,439], but the mechanisms linking ER stress with defective
autophagy, and the inflammatory response, are not clarified as of yet
[315,406,440,441]. Table 1 summarizes the main associations of autophagy with
pancreatitis.
Table 1. Main studies on the role of autophagy in pancreatitis.
7. FUTURE PERSPECTIVES
Most pre-clinical studies focus on the regulation of the increased intra acinar
calcium, and many ongoing clinical trials try to identify new agents for the
treatment of AP. Despite the fact that pharmacological inhibition of the
autophagy process offers a potential therapeutic strategy for AP, ongoing
clinical trials are not existent, and only pre-clinical studies offer potential
future clinical applications [443,444].
Inhibition of autophagy reduces AP severity [445] and alters the progression of
experimental AP in mice [446]. Earlier studies showed that activation of the
nuclear factor-κB pathway increases autophagy in pancreatic acinus cells, while
inhibition of this pathway ameliorated AP [447].
Interleukin 22, a member of the Interleukin-10 family, is the most widely used
agent in animal models. IL-22 is increased in experimental AP and in patients
with AP. Administration of IL-22 reduced pancreatic inflammation and improved
survival [448]. The protective effect of IL-22 on pancreatitis was mediated via
the induction of Bcl-2 and Bcl-XL, which bind to Beclin-1 and subsequently
inhibit autophagosome formation and the autophagic pathway [377]. A more recent
study indicated that the beneficial effect of IL-22 is due to the activation of
the AKT/mTOR pathway and subsequent inhibition of autophagy [449].
Spautin-1, an inhibitor of autophagy, was also shown to ameliorate acute
inhibiting impaired autophagy and Ca2+ overload [431]. Moreover, a spautin-1
derivative, spautin-A41, was described as a potent autophagy inhibitor. Mice
treated with spautin-A41 were resistant to cerulein-induced pancreatitis due to
the inhibition of autophagosome formation [450]. Interestingly, sitagliptin, a
dipeptidyl peptidase-4 (DPP4) inhibitor recently associated with autophagy,
ameliorated AP-induced acute lung injury. Sitagliptin protection was attributed
to the reduction of excessive autophagy through the p62-Keap1-Nrf2 signaling
pathway [381].
Clinical trials are required to verify in patients the significance of autophagy
modulators.
8. CONCLUSIONS
The pathogenesis of both acute and chronic pancreatitis is a complicated process
involving several pathways. The traditional theory of premature activation of
trypsinogen into the acinar cells has been complemented by various signals in
both acinar and ductal cells of the pancreas. Mitochondrial dysfunction and ER
stress are prominent features of pancreatitis pathophysiology. Moreover, calcium
signaling, exosome abnormalities, and the implication of mechanisms related to
inflammation, innate immunity, and genetic predisposition have been clarified.
Macrophages are recognized as important mediators of inflammation and innate
immunity. MicroRNA regulation of inflammation has also been explored. Fibrosis
induction by macrophages and pancreatic stellate cells are prominent
characteristics of disease progression towards chronic pancreatitis. Most
importantly, the role of autophagy and its specialized forms, such as mitophagy,
are now at the center of interest. Autophagy has been associated with both
protection and aggravation of experimental and human pancreatitis. It is the
common denominator behind practically every mechanism involved in the
pathogenesis of pancreatitis and a target for possible therapeutic interventions
in this disease.
AUTHOR CONTRIBUTIONS
Study concept and design (I.T. and E.K.), acquisition of data (E.K.), analysis
and interpretation of data (E.K. and A.V.), drafting of the manuscript (I.T. and
E.K.), critical revision of the manuscript for important intellectual content
(E.K. and I.T.), administrative, technical, or material support (I.T. and A.V.),
and study supervision (I.T. and E.K.). All authors have made a significant
contribution to this study and have approved the final manuscript. All authors
have read and agreed to the published version of the manuscript.
FUNDING
This research received no external funding.
CONFLICTS OF INTEREST
The authors declare no conflicts of interest.
REFERENCES
1. Yadav, D.; Lowenfels, A.B. The epidemiology of pancreatitis and pancreatic
cancer. Gastroenterology 2013, 144, 1252–1261. [Google Scholar] [CrossRef]
[PubMed]
2. Coté, G.A.; Yadav, D.; Slivka, A.; Hawes, R.H.; Anderson, M.A.; Burton,
F.R.; Brand, R.E.; Banks, P.A.; Lewis, M.D.; Disario, J.A.; et al. Alcohol
and smoking as risk factors in an epidemiology study of patients with
chronic pancreatitis. Clin. Gastroenterol. Hepatol. 2011, 9, 266–273; quiz
e27. [Google Scholar] [CrossRef] [PubMed]
3. Setiawan, V.W.; Monroe, K.; Lugea, A.; Yadav, D.; Pandol, S. Uniting
Epidemiology and Experimental Disease Models for Alcohol-Related
Pancreatic Disease. Alcohol. Res. 2017, 38, 173–182. [Google Scholar]
[PubMed]
4. Setiawan, V.W.; Pandol, S.J.; Porcel, J.; Wilkens, L.R.; Le Marchand, L.;
Pike, M.C.; Monroe, K.R. Prospective Study of Alcohol Drinking, Smoking,
and Pancreatitis: The Multiethnic Cohort. Pancreas 2016, 45, 819–825.
[Google Scholar] [CrossRef] [PubMed]
5. Yadav, D.; Hawes, R.H.; Brand, R.E.; Anderson, M.A.; Money, M.E.; Banks,
P.A.; Bishop, M.D.; Baillie, J.; Sherman, S.; DiSario, J.; et al. Alcohol
consumption, cigarette smoking, and the risk of recurrent acute and
chronic pancreatitis. Arch. Intern. Med. 2009, 169, 1035–1045. [Google
Scholar] [CrossRef] [PubMed]
6. Boxhoorn, L.; Voermans, R.P.; Bouwense, S.A.; Bruno, M.J.; Verdonk, R.C.;
Boermeester, M.A.; van Santvoort, H.C.; Besselink, M.G. Acute
pancreatitis. Lancet 2020, 396, 726–734. [Google Scholar] [CrossRef]
[PubMed]
7. Valdivielso, P.; Ramírez-Bueno, A.; Ewald, N. Current knowledge of
hypertriglyceridemic pancreatitis. Eur. J. Intern. Med. 2014, 25, 689–694.
[Google Scholar] [CrossRef] [PubMed]
8. Adiamah, A.; Psaltis, E.; Crook, M.; Lobo, D.N. A systematic review of the
epidemiology, pathophysiology and current management of hyperlipidaemic
pancreatitis. Clin. Nutr. 2018, 37 Pt A, 1810–1822. [Google Scholar]
[CrossRef]
9. Roberts, S.E.; Morrison-Rees, S.; John, A.; Williams, J.G.; Brown, T.H.;
Samuel, D.G. The incidence and aetiology of acute pancreatitis across
Europe. Pancreatology 2017, 17, 155–165. [Google Scholar] [CrossRef]
[PubMed]
10. Gonzalez-Perez, A.; Schlienger, R.G.; Rodríguez, L.A. Acute pancreatitis
in association with type 2 diabetes and antidiabetic drugs: A
population-based cohort study. Diabetes Care 2010, 33, 2580–2585. [Google
Scholar] [CrossRef] [PubMed]
11. Lai, S.W.; Muo, C.H.; Liao, K.F.; Sung, F.C.; Chen, P.C. Risk of acute
pancreatitis in type 2 diabetes and risk reduction on anti-diabetic drugs:
A population-based cohort study in Taiwan. Am. J. Gastroenterol. 2011,
106, 1697–1704. [Google Scholar] [CrossRef] [PubMed]
12. Shafqet, M.; Sharzehi, K. Diabetes and the Pancreatobiliary Diseases.
Curr. Treat. Options Gastroenterol. 2017, 15, 508–519. [Google Scholar]
[CrossRef] [PubMed]
13. Forsmark, C.E.; Vege, S.S.; Wilcox, C.M. Acute Pancreatitis. N. Engl. J.
Med. 2017, 376, 598–599. [Google Scholar] [CrossRef] [PubMed]
14. Jalaly, N.Y.; Moran, R.A.; Fargahi, F.; Khashab, M.A.; Kamal, A.; Lennon,
A.M.; Walsh, C.; Makary, M.A.; Whitcomb, D.C.; Yadav, D.; et al. An
Evaluation of Factors Associated With Pathogenic PRSS1, SPINK1, CTFR,
and/or CTRC Genetic Variants in Patients With Idiopathic Pancreatitis. Am.
J. Gastroenterol. 2017, 112, 1320–1329. [Google Scholar] [CrossRef]
[PubMed]
15. Whitcomb, D.C. Genetic risk factors for pancreatic disorders.
Gastroenterology 2013, 144, 1292–1302. [Google Scholar] [CrossRef]
[PubMed]
16. Whitcomb, D.C.; LaRusch, J.; Krasinskas, A.M.; Klei, L.; Smith, J.P.;
Brand, R.E.; Neoptolemos, J.P.; Lerch, M.M.; Tector, M.; Sandhu, B.S.; et
al. Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk
for alcohol-related and sporadic pancreatitis. Nat. Genet. 2012, 44,
1349–1354. [Google Scholar] [CrossRef] [PubMed]
17. Sankaran, S.J.; Xiao, A.Y.; Wu, L.M.; Windsor, J.A.; Forsmark, C.E.;
Petrov, M.S. Frequency of progression from acute to chronic pancreatitis
and risk factors: A meta-analysis. Gastroenterology 2015, 149,
1490–1500.e1. [Google Scholar] [CrossRef] [PubMed]
18. Whitcomb, D.C.; Frulloni, L.; Garg, P.; Greer, J.B.; Schneider, A.; Yadav,
D.; Shimosegawa, T. Chronic pancreatitis: An international draft consensus
proposal for a new mechanistic definition. Pancreatology 2016, 16,
218–224. [Google Scholar] [CrossRef] [PubMed]
19. Kleeff, J.; Whitcomb, D.C.; Shimosegawa, T.; Esposito, I.; Lerch, M.M.;
Gress, T.; Mayerle, J.; Drewes, A.M.; Rebours, V.; Akisik, F.; et al.
Chronic pancreatitis. Nat. Rev. Dis. Primers. 2017, 3, 17060. [Google
Scholar] [CrossRef] [PubMed]
20. Beyer, G.; Habtezion, A.; Werner, J.; Lerch, M.M.; Mayerle, J. Chronic
pancreatitis. Lancet 2020, 396, 499–512. [Google Scholar] [CrossRef]
[PubMed]
21. Vege, S.S.; Chari, S.T. Chronic Pancreatitis. N. Engl. J. Med. 2022, 386,
869–878. [Google Scholar] [CrossRef] [PubMed]
22. Singh, V.K.; Yadav, D.; Garg, P.K. Diagnosis and Management of Chronic
Pancreatitis: A Review. JAMA 2019, 322, 2422–2434. [Google Scholar]
[CrossRef] [PubMed]
23. Jeon, C.Y.; Whitcomb, D.C.; Slivka, A.; Brand, R.E.; Gelrud, A.; Tang, G.;
Abberbock, J.; AlKaade, S.; Guda, N.; Mel Wilcox, C.; et al. Lifetime
Drinking History of Persons With Chronic Pancreatitis. Alcohol. Alcohol.
2019, 54, 615–624. [Google Scholar] [CrossRef] [PubMed]
24. Strum, W.B. Abstinence in alcoholic chronic pancreatitis. Effect on pain
and outcome. J. Clin. Gastroenterol. 1995, 20, 37–41. [Google Scholar]
[CrossRef] [PubMed]
25. Strum, W.B.; Spiro, H.M. Chronic pancreatitis. Ann. Intern. Med. 1971, 74,
264–277. [Google Scholar] [CrossRef] [PubMed]
26. Mayerle, J.; Sendler, M.; Hegyi, E.; Beyer, G.; Lerch, M.M.; Sahin-Tóth,
M. Genetics, Cell Biology, and Pathophysiology of Pancreatitis.
Gastroenterology 2019, 156, 1951–1968.e1. [Google Scholar] [CrossRef]
[PubMed]
27. Masamune, A.; Kotani, H.; Sörgel, F.L.; Chen, J.M.; Hamada, S.; Sakaguchi,
R.; Masson, E.; Nakano, E.; Kakuta, Y.; Niihori, T.; et al. Variants That
Affect Function of Calcium Channel TRPV6 Are Associated With Early-Onset
Chronic Pancreatitis. Gastroenterology 2020, 158, 1626–1641.e8. [Google
Scholar] [CrossRef] [PubMed]
28. Sahin-Tóth, M. Channelopathy of the Pancreas Causes Chronic Pancreatitis.
Gastroenterology 2020, 158, 1538–1540. [Google Scholar] [CrossRef]
[PubMed]
29. Habtezion, A.; Gukovskaya, A.S.; Pandol, S.J. Acute Pancreatitis: A
Multifaceted Set of Organelle and Cellular Interactions. Gastroenterology
2019, 156, 1941–1950. [Google Scholar] [CrossRef] [PubMed]
30. Saluja, A.; Dudeja, V.; Dawra, R.; Sah, R.P. Early Intra-Acinar Events in
Pathogenesis of Pancreatitis. Gastroenterology 2019, 156, 1979–1993.
[Google Scholar] [CrossRef] [PubMed]
31. Pitchumoni, C.S.; Glasser, M.; Saran, R.M.; Panchacharam, P.; Thelmo, W.
Pancreatic fibrosis in chronic alcoholics and nonalcoholics without
clinical pancreatitis. Am. J. Gastroenterol. 1984, 79, 382–388. [Google
Scholar] [PubMed]
32. Hori, Y.; Vege, S.S.; Chari, S.T.; Gleeson, F.C.; Levy, M.J.; Pearson,
R.K.; Petersen, B.T.; Kendrick, M.L.; Takahashi, N.; Truty, M.J.; et al.
Classic chronic pancreatitis is associated with prior acute pancreatitis
in only 50% of patients in a large single-institution study. Pancreatology
2019, 19, 224–229. [Google Scholar] [CrossRef] [PubMed]
33. Ktistakis, N.T. In praise of M. Anselmier who first used the term
“autophagie” in 1859. Autophagy 2017, 13, 2015–2017. [Google Scholar]
[CrossRef] [PubMed]
34. Appelmans, F.; Wattiaux, R.; De Duve, C. Tissue fractionation studies. 5.
The association of acid phosphatase with a special class of cytoplasmic
granules in rat liver. Biochem. J. 1955, 59, 438–445. [Google Scholar]
[CrossRef] [PubMed]
35. de Duve, C. The lysosome turns fifty. Nat. Cell Biol. 2005, 7, 847–849.
[Google Scholar] [CrossRef] [PubMed]
36. Takeshige, K.; Baba, M.; Tsuboi, S.; Noda, T.; Ohsumi, Y. Autophagy in
yeast demonstrated with proteinase-deficient mutants and conditions for
its induction. J. Cell Biol. 1992, 119, 301–311. [Google Scholar]
[CrossRef]
37. Klionsky, D.J.; Baehrecke, E.H.; Brumell, J.H.; Chu, C.T.; Codogno, P.;
Cuervo, A.M.; Debnath, J.; Deretic, V.; Elazar, Z.; Eskelinen, E.L.; et
al. A comprehensive glossary of autophagy-related molecules and processes
(2nd edition). Autophagy 2011, 7, 1273–1294. [Google Scholar] [CrossRef]
[PubMed]
38. Harnett, M.M.; Pineda, M.A.; Latré de Laté, P.; Eason, R.J.; Besteiro, S.;
Harnett, W.; Langsley, G. From Christian de Duve to Yoshinori Ohsumi: More
to autophagy than just dining at home. Biomed. J. 2017, 40, 9–22. [Google
Scholar] [CrossRef] [PubMed]
39. Ohsumi, Y. Historical landmarks of autophagy research. Cell Res. 2014, 24,
9–23. [Google Scholar] [CrossRef] [PubMed]
40. Gonzalez Porras, M.A.; Sieck, G.C.; Mantilla, C.B. Impaired Autophagy in
Motor Neurons: A Final Common Mechanism of Injury and Death. Physiology
2018, 33, 211–224. [Google Scholar] [CrossRef] [PubMed]
41. Corona Velazquez, A.F.; Jackson, W.T. So Many Roads: The Multifaceted
Regulation of Autophagy Induction. Mol. Cell Biol. 2018, 38, e00303-18.
[Google Scholar] [CrossRef] [PubMed]
42. Liang, N.; He, Q.; Liu, X.; Sun, H. Multifaceted roles of ATM in
autophagy: From nonselective autophagy to selective autophagy. Cell
Biochem. Funct. 2019, 37, 177–184. [Google Scholar] [CrossRef] [PubMed]
43. Zachari, M.; Ganley, I.G. The mammalian ULK1 complex and autophagy
initiation. Essays Biochem. 2017, 61, 585–596. [Google Scholar] [CrossRef]
[PubMed]
44. Kim, J.; Kundu, M.; Viollet, B.; Guan, K.L. AMPK and mTOR regulate
autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 2011,
13, 132–141. [Google Scholar] [CrossRef]
45. Russell, R.C.; Tian, Y.; Yuan, H.; Park, H.W.; Chang, Y.Y.; Kim, J.; Kim,
H.; Neufeld, T.P.; Dillin, A.; Guan, K.L. ULK1 induces autophagy by
phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nat. Cell
Biol. 2013, 15, 741–750. [Google Scholar] [CrossRef] [PubMed]
46. Ren, H.; Zhao, F.; Zhang, Q.; Huang, X.; Wang, Z. Autophagy and skin wound
healing. Burn. Trauma. 2022, 10, tkac003. [Google Scholar] [CrossRef]
[PubMed]
47. Birgisdottir, Å.B.; Johansen, T. Autophagy and
endocytosis—Interconnections and interdependencies. J. Cell Sci. 2020,
133, jcs228114. [Google Scholar] [CrossRef]
48. Levine, B.; Sinha, S.; Kroemer, G. Bcl-2 family members: Dual regulators
of apoptosis and autophagy. Autophagy 2008, 4, 600–606. [Google Scholar]
[CrossRef] [PubMed]
49. Kang, R.; Zeh, H.J.; Lotze, M.T.; Tang, D. The Beclin 1 network regulates
autophagy and apoptosis. Cell Death Differ. 2011, 18, 571–580. [Google
Scholar] [CrossRef]
50. Parzych, K.R.; Klionsky, D.J. An overview of autophagy: Morphology,
mechanism, and regulation. Antioxid. Redox Signal. 2014, 20, 460–473.
[Google Scholar] [CrossRef]
51. Dikic, I.; Elazar, Z. Mechanism and medical implications of mammalian
autophagy. Nat. Rev. Mol. Cell Biol. 2018, 19, 349–364. [Google Scholar]
[CrossRef] [PubMed]
52. Cheng, X.; Ma, X.; Ding, X.; Li, L.; Jiang, X.; Shen, Z.; Chen, S.; Liu,
W.; Gong, W.; Sun, Q. Pacer Mediates the Function of Class III PI3K and
HOPS Complexes in Autophagosome Maturation by Engaging Stx17. Mol. Cell.
2017, 65, 1029–1043.e5. [Google Scholar] [CrossRef] [PubMed]
53. Cheng, X.; Ma, X.; Zhu, Q.; Song, D.; Ding, X.; Li, L.; Jiang, X.; Wang,
X.; Tian, R.; Su, H.; et al. Pacer Is a Mediator of mTORC1 and GSK3-TIP60
Signaling in Regulation of Autophagosome Maturation and Lipid Metabolism.
Mol. Cell 2019, 73, 788–802.e7. [Google Scholar] [CrossRef]
54. Sheng, J.Q.; Wang, M.R.; Fang, D.; Liu, L.; Huang, W.J.; Tian, D.A.; He,
X.X.; Li, P.Y. LncRNA NBR2 inhibits tumorigenesis by regulating autophagy
in hepatocellular carcinoma. Biomed. Pharmacother. 2021, 133, 111023.
[Google Scholar] [CrossRef] [PubMed]
55. Di Malta, C.; Cinque, L.; Settembre, C. Transcriptional Regulation of
Autophagy: Mechanisms and Diseases. Front. Cell Dev. Biol. 2019, 7, 114.
[Google Scholar] [CrossRef] [PubMed]
56. Galluzzi, L.; Green, D.R. Autophagy-Independent Functions of the Autophagy
Machinery. Cell 2019, 177, 1682–1699. [Google Scholar] [CrossRef] [PubMed]
57. Shahrabi, S.; Paridar, M.; Zeinvand-Lorestani, M.; Jalili, A.; Zibara, K.;
Abdollahi, M.; Khosravi, A. Autophagy regulation and its role in normal
and malignant hematopoiesis. J. Cell Physiol. 2019, 234, 21746–21757.
[Google Scholar] [CrossRef] [PubMed]
58. Thorburn, A. Autophagy and disease. J. Biol. Chem. 2018, 293, 5425–5430.
[Google Scholar] [CrossRef] [PubMed]
59. Nakamura, S.; Yoshimori, T. New insights into autophagosome-lysosome
fusion. J. Cell Sci. 2017, 130, 1209–1216. [Google Scholar] [CrossRef]
[PubMed]
60. Katsuragi, Y.; Ichimura, Y.; Komatsu, M. p62/SQSTM1 functions as a
signaling hub and an autophagy adaptor. FEBS J. 2015, 282, 4672–4678.
[Google Scholar] [CrossRef]
61. Itakura, E.; Kishi-Itakura, C.; Mizushima, N. The hairpin-type
tail-anchored SNARE syntaxin 17 targets to autophagosomes for fusion with
endosomes/lysosomes. Cell 2012, 151, 1256–1269. [Google Scholar]
[CrossRef] [PubMed]
62. Matsui, T.; Jiang, P.; Nakano, S.; Sakamaki, Y.; Yamamoto, H.; Mizushima,
N. Autophagosomal YKT6 is required for fusion with lysosomes independently
of syntaxin 17. J. Cell Biol. 2018, 217, 2633–2645. [Google Scholar]
[CrossRef] [PubMed]
63. Hegedűs, K.; Takáts, S.; Boda, A.; Jipa, A.; Nagy, P.; Varga, K.; Kovács,
A.L.; Juhász, G. The Ccz1-Mon1-Rab7 module and Rab5 control distinct steps
of autophagy. Mol. Biol. Cell. 2016, 27, 3132–3142. [Google Scholar]
[CrossRef] [PubMed]
64. Vaites, L.P.; Paulo, J.A.; Huttlin, E.L.; Harper, J.W. Systematic Analysis
of Human Cells Lacking ATG8 Proteins Uncovers Roles for GABARAPs and the
CCZ1/MON1 Regulator C18orf8/RMC1 in Macroautophagic and Selective
Autophagic Flux. Mol. Cell Biol. 2017, 38, e00392-17. [Google Scholar]
[CrossRef] [PubMed]
65. Ferguson, C.J.; Lenk, G.M.; Meisler, M.H. Defective autophagy in neurons
and astrocytes from mice deficient in PI(3,5)P2. Hum. Mol. Genet. 2009,
18, 4868–4878. [Google Scholar] [CrossRef] [PubMed]
66. Gómez-Virgilio, L.; Silva-Lucero, M.D.; Flores-Morelos, D.S.;
Gallardo-Nieto, J.; Lopez-Toledo, G.; Abarca-Fernandez, A.M.;
Zacapala-Gómez, A.E.; Luna-Muñoz, J.; Montiel-Sosa, F.; Soto-Rojas, L.O.;
et al. Autophagy: A Key Regulator of Homeostasis and Disease: An Overview
of Molecular Mechanisms and Modulators. Cells 2022, 11, 2262. [Google
Scholar] [CrossRef] [PubMed]
67. Peña-Llopis, S.; Vega-Rubin-de-Celis, S.; Schwartz, J.C.; Wolff, N.C.;
Tran, T.A.; Zou, L.; Xie, X.J.; Corey, D.R.; Brugarolas, J. Regulation of
TFEB and V-ATPases by mTORC1. EMBO J. 2011, 30, 3242–3258. [Google
Scholar] [CrossRef] [PubMed]
68. Yu, L.; McPhee, C.K.; Zheng, L.; Mardones, G.A.; Rong, Y.; Peng, J.; Mi,
N.; Zhao, Y.; Liu, Z.; Wan, F.; et al. Termination of autophagy and
reformation of lysosomes regulated by mTOR. Nature 2010, 465, 942–946.
[Google Scholar] [CrossRef] [PubMed]
69. Puertollano, R.; Ferguson, S.M.; Brugarolas, J.; Ballabio, A. The complex
relationship between TFEB transcription factor phosphorylation and
subcellular localization. EMBO J. 2018, 37, e98804. [Google Scholar]
[CrossRef] [PubMed]
70. Settembre, C.; Di Malta, C.; Polito, V.A.; Garcia Arencibia, M.; Vetrini,
F.; Erdin, S.; Erdin, S.U.; Huynh, T.; Medina, D.; Colella, P.; et al.
TFEB links autophagy to lysosomal biogenesis. Science 2011, 332,
1429–1433. [Google Scholar] [CrossRef] [PubMed]
71. Yan, S. Role of TFEB in Autophagy and the Pathogenesis of Liver Diseases.
Biomolecules 2022, 12, 672. [Google Scholar] [CrossRef] [PubMed]
72. Barthez, M.; Poplineau, M.; Elrefaey, M.; Caruso, N.; Graba, Y.; Saurin,
A.J. Human ZKSCAN3 and Drosophila M1BP are functionally homologous
transcription factors in autophagy regulation. Sci. Rep. 2020, 10, 9653.
[Google Scholar] [CrossRef] [PubMed]
73. Pan, H.Y.; Valapala, M. Role of the Transcriptional Repressor Zinc Finger
with KRAB and SCAN Domains 3 (ZKSCAN3) in Retinal Pigment Epithelial
Cells. Cells 2021, 10, 2504. [Google Scholar] [CrossRef] [PubMed]
74. Kim, S.; Eun, H.S.; Jo, E.K. Roles of Autophagy-Related Genes in the
Pathogenesis of Inflammatory Bowel Disease. Cells 2019, 8, 77. [Google
Scholar] [CrossRef] [PubMed]
75. Rudnik, S.; Damme, M. The lysosomal membrane-export of metabolites and
beyond. FEBS J. 2021, 288, 4168–4182. [Google Scholar] [CrossRef] [PubMed]
76. Codogno, P.; Mehrpour, M.; Proikas-Cezanne, T. Canonical and non-canonical
autophagy: Variations on a common theme of self-eating? Nat. Rev. Mol.
Cell Biol. 2011, 13, 7–12. [Google Scholar] [CrossRef] [PubMed]
77. Heckmann, B.L.; Boada-Romero, E.; Cunha, L.D.; Magne, J.; Green, D.R.
LC3-Associated Phagocytosis and Inflammation. J. Mol. Biol. 2017, 429,
3561–3576. [Google Scholar] [CrossRef] [PubMed]
78. Martinez, J. LAP it up, fuzz ball: A short history of LC3-associated
phagocytosis. Curr. Opin. Immunol. 2018, 55, 54–61. [Google Scholar]
[CrossRef] [PubMed]
79. Münz, C. Non-canonical Functions of Macroautophagy Proteins During
Endocytosis by Myeloid Antigen Presenting Cells. Front. Immunol. 2018, 9,
2765. [Google Scholar] [CrossRef]
80. Heckmann, B.L.; Green, D.R. LC3-associated phagocytosis at a glance. J.
Cell Sci. 2019, 132, jcs222984. [Google Scholar] [CrossRef] [PubMed]
81. Durgan, J.; Florey, O. A new flavor of cellular Atg8-family protein
lipidation—alternative conjugation to phosphatidylserine during CASM.
Autophagy 2021, 17, 2642–2644. [Google Scholar] [CrossRef] [PubMed]
82. Durgan, J.; Lystad, A.H.; Sloan, K.; Carlsson, S.R.; Wilson, M.I.;
Marcassa, E.; Ulferts, R.; Webster, J.; Lopez-Clavijo, A.F.; Wakelam,
M.J.; et al. Non-canonical autophagy drives alternative ATG8 conjugation
to phosphatidylserine. Mol. Cell. 2021, 81, 2031–2040.e8. [Google Scholar]
[CrossRef] [PubMed]
83. Foerster, E.G.; Mukherjee, T.; Cabral-Fernandes, L.; Rocha, J.D.B.;
Girardin, S.E.; Philpott, D.J. How autophagy controls the intestinal
epithelial barrier. Autophagy 2022, 18, 86–103. [Google Scholar]
[CrossRef] [PubMed]
84. Youle, R.J.; Narendra, D.P. Mechanisms of mitophagy. Nat. Rev. Mol. Cell
Biol. 2011, 12, 9–14. [Google Scholar] [CrossRef] [PubMed]
85. Frank, M.; Duvezin-Caubet, S.; Koob, S.; Occhipinti, A.; Jagasia, R.;
Petcherski, A.; Ruonala, M.O.; Priault, M.; Salin, B.; Reichert, A.S.
Mitophagy is triggered by mild oxidative stress in a mitochondrial fission
dependent manner. Biochim. Biophys. Acta 2012, 1823, 2297–2310. [Google
Scholar] [CrossRef]
86. Ryter, S.W.; Bhatia, D.; Choi, M.E. Autophagy: A Lysosome-Dependent
Process with Implications in Cellular Redox Homeostasis and Human Disease.
Antioxid. Redox Signal. 2019, 30, 138–159. [Google Scholar] [CrossRef]
[PubMed]
87. Durcan, T.M.; Fon, E.A. The three ‘P’s of mitophagy: PARKIN, PINK1, and
post-translational modifications. Genes Dev. 2015, 29, 989–999. [Google
Scholar] [CrossRef] [PubMed]
88. Narendra, D.P.; Jin, S.M.; Tanaka, A.; Suen, D.F.; Gautier, C.A.; Shen,
J.; Cookson, M.R.; Youle, R.J. PINK1 is selectively stabilized on impaired
mitochondria to activate Parkin. PLoS Biol. 2010, 8, e1000298. [Google
Scholar] [CrossRef] [PubMed]
89. Kondapalli, C.; Kazlauskaite, A.; Zhang, N.; Woodroof, H.I.; Campbell,
D.G.; Gourlay, R.; Burchell, L.; Walden, H.; Macartney, T.J.; Deak, M.; et
al. PINK1 is activated by mitochondrial membrane potential depolarization
and stimulates Parkin E3 ligase activity by phosphorylating Serine 65.
Open Biol. 2012, 2, 120080. [Google Scholar] [CrossRef] [PubMed]
90. Koyano, F.; Okatsu, K.; Kosako, H.; Tamura, Y.; Go, E.; Kimura, M.;
Kimura, Y.; Tsuchiya, H.; Yoshihara, H.; Hirokawa, T.; et al. Ubiquitin is
phosphorylated by PINK1 to activate parkin. Nature 2014, 510, 162–166.
[Google Scholar] [CrossRef] [PubMed]
91. Geisler, S.; Holmström, K.M.; Skujat, D.; Fiesel, F.C.; Rothfuss, O.C.;
Kahle, P.J.; Springer, W. PINK1/Parkin-mediated mitophagy is dependent on
VDAC1 and p62/SQSTM1. Nat. Cell Biol. 2010, 12, 119–131. [Google Scholar]
[CrossRef] [PubMed]
92. Chen, Y.; Dorn, G.W., 2nd. PINK1-phosphorylated mitofusin 2 is a Parkin
receptor for culling damaged mitochondria. Science. 2013, 340, 471–475.
[Google Scholar] [CrossRef] [PubMed]
93. Lazarou, M.; Sliter, D.A.; Kane, L.A.; Sarraf, S.A.; Wang, C.; Burman,
J.L.; Sideris, D.P.; Fogel, A.I.; Youle, R.J. The ubiquitin kinase PINK1
recruits autophagy receptors to induce mitophagy. Nature 2015, 524,
309–314. [Google Scholar] [CrossRef]
94. Richter, B.; Sliter, D.A.; Herhaus, L.; Stolz, A.; Wang, C.; Beli, P.;
Zaffagnini, G.; Wild, P.; Martens, S.; Wagner, S.A.; et al.
Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and
promotes selective autophagy of damaged mitochondria. Proc. Natl. Acad.
Sci. USA 2016, 113, 4039–4044. [Google Scholar] [CrossRef] [PubMed]
95. Moore, A.S.; Holzbaur, E.L. Dynamic recruitment and activation of
ALS-associated TBK1 with its target optineurin are required for efficient
mitophagy. Proc. Natl. Acad. Sci. USA 2016, 113, E3349–E3358. [Google
Scholar] [CrossRef] [PubMed]
96. Yao, R.Q.; Ren, C.; Xia, Z.F.; Yao, Y.M. Organelle-specific autophagy in
inflammatory diseases: A potential therapeutic target underlying the
quality control of multiple organelles. Autophagy 2021, 17, 385–401.
[Google Scholar] [CrossRef] [PubMed]
97. Xu, Y.; Shen, J.; Ran, Z. Emerging views of mitophagy in immunity and
autoimmune diseases. Autophagy 2020, 16, 3–17. [Google Scholar] [CrossRef]
[PubMed]
98. Ke, P.Y. Mitophagy in the Pathogenesis of Liver Diseases. Cells 2020, 9,
831. [Google Scholar] [CrossRef] [PubMed]
99. Alim Al-Bari, A.; Ito, Y.; Thomes, P.G.; Menon, M.B.; García-Macia, M.;
Fadel, R.; Stadlin, A.; Peake, N.; Faris, M.E.; Eid, N.; et al. Emerging
mechanistic insights of selective autophagy in hepatic diseases. Front.
Pharmacol. 2023, 14, 1149809. [Google Scholar] [CrossRef] [PubMed]
100. Onishi, M.; Yamano, K.; Sato, M.; Matsuda, N.; Okamoto, K. Molecular
mechanisms and physiological functions of mitophagy. EMBO J. 2021, 40,
e104705. [Google Scholar] [CrossRef] [PubMed]
101. Puleston, D.J.; Simon, A.K. Autophagy in the immune system. Immunology
2014, 141, 1–8. [Google Scholar] [CrossRef]
102. Liu, K.; Zhao, E.; Ilyas, G.; Lalazar, G.; Lin, Y.; Haseeb, M.; Tanaka,
K.E.; Czaja, M.J. Impaired macrophage autophagy increases the immune
response in obese mice by promoting proinflammatory macrophage
polarization. Autophagy 2015, 11, 271–284. [Google Scholar] [CrossRef]
[PubMed]
103. Gutierrez, M.G.; Master, S.S.; Singh, S.B.; Taylor, G.A.; Colombo, M.I.;
Deretic, V. Autophagy is a defense mechanism inhibiting BCG and
Mycobacterium tuberculosis survival in infected macrophages. Cell 2004,
119, 753–766. [Google Scholar] [CrossRef]
104. Oh, J.E.; Lee, H.K. Autophagy as an innate immune modulator. Immune. Netw.
2013, 13, 1–9. [Google Scholar] [CrossRef] [PubMed]
105. Wei, J.; Long, L.; Yang, K.; Guy, C.; Shrestha, S.; Chen, Z.; Wu, C.;
Vogel, P.; Neale, G.; Green, D.R.; et al. Autophagy enforces functional
integrity of regulatory T cells by coupling environmental cues and
metabolic homeostasis. Nat. Immunol. 2016, 17, 277–285. [Google Scholar]
[CrossRef] [PubMed]
106. Peral de Castro, C.; Jones, S.A.; Ní Cheallaigh, C.; Hearnden, C.A.;
Williams, L.; Winter, J.; Lavelle, E.C.; Mills, K.H.; Harris, J. Autophagy
regulates IL-23 secretion and innate T cell responses through effects on
IL-1 secretion. J. Immunol. 2012, 189, 4144–4153. [Google Scholar]
[CrossRef] [PubMed]
107. Yonekawa, T.; Thorburn, A. Autophagy and cell death. Essays Biochem. 2013,
55, 105–117. [Google Scholar]
108. Nikoletopoulou, V.; Markaki, M.; Palikaras, K.; Tavernarakis, N. Crosstalk
between apoptosis, necrosis and autophagy. Biochim Biophys. Acta 2013,
1833, 3448–3459. [Google Scholar] [CrossRef] [PubMed]
109. Mariño, G.; Niso-Santano, M.; Baehrecke, E.H.; Kroemer, G.
Self-consumption: The interplay of autophagy and apoptosis. Nat. Rev. Mol.
Cell Biol. 2014, 15, 81–94. [Google Scholar] [CrossRef] [PubMed]
110. Ni, H.M.; Bockus, A.; Boggess, N.; Jaeschke, H.; Ding, W.X. Activation of
autophagy protects against acetaminophen-induced hepatotoxicity.
Hepatology 2012, 55, 222–232. [Google Scholar] [CrossRef] [PubMed]
111. Liang, Q.; Xiao, Y.; Liu, K.; Zhong, C.; Zeng, M.; Xiao, F. Cr(VI)-Induced
Autophagy Protects L-02 Hepatocytes from Apoptosis Through the
ROS-AKT-mTOR Pathway. Cell Physiol. Biochem. 2018, 51, 1863–1878. [Google
Scholar] [CrossRef] [PubMed]
112. Zhou, B.; Liu, J.; Kang, R.; Klionsky, D.J.; Kroemer, G.; Tang, D.
Ferroptosis is a type of autophagy-dependent cell death. Semin. Cancer
Biol. 2020, 66, 89–100. [Google Scholar] [CrossRef] [PubMed]
113. Liu, J.; Kuang, F.; Kroemer, G.; Klionsky, D.J.; Kang, R.; Tang, D.
Autophagy-Dependent Ferroptosis: Machinery and Regulation. Cell Chem.
Biol. 2020, 27, 420–435. [Google Scholar] [CrossRef] [PubMed]
114. Hou, W.; Xie, Y.; Song, X.; Sun, X.; Lotze, M.T.; Zeh, H.J., 3rd; Kang,
R.; Tang, D. Autophagy promotes ferroptosis by degradation of ferritin.
Autophagy 2016, 12, 1425–1428. [Google Scholar] [CrossRef] [PubMed]
115. Kang, R.; Tang, D. Autophagy and Ferroptosis—What’s the Connection? Curr.
Pathobiol. Rep. 2017, 5, 153–159. [Google Scholar] [CrossRef] [PubMed]
116. Qu, X.; Gao, H.; Tao, L.; Zhang, Y.; Zhai, J.; Song, Y.; Zhang, S.
Autophagy inhibition-enhanced assembly of the NLRP3 inflammasome is
associated with cisplatin-induced acute injury to the liver and kidneys in
rats. J. Biochem. Mol. Toxicol. 2018, 33, e22208. [Google Scholar]
[CrossRef] [PubMed]
117. Chang, Y.P.; Ka, S.M.; Hsu, W.H.; Chen, A.; Chao, L.K.; Lin, C.C.; Hsieh,
C.C.; Chen, M.C.; Chiu, H.W.; Ho, C.L.; et al. Resveratrol inhibits NLRP3
inflammasome activation by preserving mitochondrial integrity and
augmenting autophagy. J. Cell Physiol. 2015, 230, 1567–1579. [Google
Scholar] [CrossRef] [PubMed]
118. de Lavera, I.; Pavon, A.D.; Paz, M.V.; Oropesa-Avila, M.; de la Mata, M.;
Alcocer-Gomez, E.; Garrido-Maraver, J.; Cotan, D.; Alvarez-Cordoba, M.;
Sanchez-Alcazar, J.A. The Connections Among Autophagy, Inflammasome and
Mitochondria. Curr. Drug Targets. 2017, 18, 1030–1038. [Google Scholar]
[CrossRef] [PubMed]
119. Broz, P.; Dixit, V.M. Inflammasomes: Mechanism of assembly, regulation and
signalling. Nat. Rev. Immunol. 2016, 16, 407–420. [Google Scholar]
[CrossRef] [PubMed]
120. Wang, X.; Jiang, L.; Shi, L.; Yao, K.; Sun, X.; Yang, G.; Jiang, L.;
Zhang, C.; Wang, N.; Zhang, H.; et al. Zearalenone induces NLRP3-dependent
pyroptosis via activation of NF-κB modulated by autophagy in INS-1 cells.
Toxicology 2019, 428, 152304. [Google Scholar] [CrossRef] [PubMed]
121. Wang, Z.; Zhang, S.; Xiao, Y.; Zhang, W.; Wu, S.; Qin, T.; Yue, Y.; Qian,
W.; Li, L. NLRP3 Inflammasome and Inflammatory Diseases. Oxid Med. Cell
Longev. 2020, 2020, 4063562. [Google Scholar] [CrossRef] [PubMed]
122. Biczo, G.; Vegh, E.T.; Shalbueva, N.; Mareninova, O.A.; Elperin, J.;
Lotshaw, E.; Gretler, S.; Lugea, A.; Malla, S.R.; Dawson, D.; et al.
Mitochondrial Dysfunction, Through Impaired Autophagy, Leads to
Endoplasmic Reticulum Stress, Deregulated Lipid Metabolism, and
Pancreatitis in Animal Models. Gastroenterology 2018, 154, 689–703.
[Google Scholar] [CrossRef] [PubMed]
123. Li, H.; Wu, D.; Zhang, H.; Li, P. New insights into regulatory cell death
and acute pancreatitis. Heliyon 2023, 9, e18036. [Google Scholar]
[CrossRef] [PubMed]
124. Zheng, Z.; Ding, Y.X.; Qu, Y.X.; Cao, F.; Li, F. A narrative review of
acute pancreatitis and its diagnosis, pathogenetic mechanism, and
management. Ann. Transl. Med. 2021, 9, 69. [Google Scholar] [CrossRef]
[PubMed]
125. Guo, X.Y.; Xiao, F.; Li, J.; Zhou, Y.N.; Zhang, W.J.; Sun, B.; Wang, G.
Exosomes and pancreatic diseases: Status, challenges, and hopes. Int. J.
Biol. Sci. 2019, 15, 1846–1860. [Google Scholar] [CrossRef] [PubMed]
126. Hegyi, P.; Petersen, O.H. The exocrine pancreas: The acinar-ductal tango
in physiology and pathophysiology. Rev. Physiol. Biochem. Pharmacol. 2013,
165, 1–30. [Google Scholar] [CrossRef] [PubMed]
127. Hegyi, P.; Rakonczay, Z. Insufficiency of electrolyte and fluid secretion
by pancreatic ductal cells leads to increased patient risk for
pancreatitis. Am. J. Gastroenterol. 2010, 105, 2119–2120. [Google Scholar]
[CrossRef] [PubMed]
128. Czakó, L.; Yamamoto, M.; Otsuki, M. Pancreatic fluid hypersecretion in
rats after acute pancreatitis. Dig. Dis. Sci. 1997, 42, 265–272. [Google
Scholar] [CrossRef] [PubMed]
129. Manso, M.A.; San Román, J.I.; de Dios, I.; García, L.J.; López, M.A.
Cerulein-induced acute pancreatitis in the rat. Study of pancreatic
secretion and plasma VIP and secretin levels. Dig. Dis. Sci. 1992, 37,
364–368. [Google Scholar] [CrossRef] [PubMed]
130. Renner, I.G.; Wisner, J.R., Jr. Ceruletide-induced acute pancreatitis in
the dog and its amelioration by exogenous secretin. Int. J. Pancreatol.
1986, 1, 39–49. [Google Scholar] [CrossRef] [PubMed]
131. Niederau, C.; Liddle, R.A.; Ferrell, L.D.; Grendell, J.H. Beneficial
effects of cholecystokinin-receptor blockade and inhibition of proteolytic
enzyme activity in experimental acute hemorrhagic pancreatitis in mice.
Evidence for cholecystokinin as a major factor in the development of acute
pancreatitis. J. Clin. Investig. 1986, 78, 1056–1063. [Google Scholar]
[CrossRef]
132. Lankisch, P.G.; Göke, B.; Fölsch, U.R.; Winckler, K.; Otto, J.;
Creutzfeldt, W. Influence of secretin on the course of acute experimental
pancreatitis in rats. Digestion 1983, 26, 187–191. [Google Scholar]
[CrossRef]
133. Lerch, M.M.; Saluja, A.K.; Rünzi, M.; Dawra, R.; Steer, M.L. Luminal
endocytosis and intracellular targeting by acinar cells during early
biliary pancreatitis in the opossum. J. Clin. Investig. 1995, 95,
2222–2231. [Google Scholar] [CrossRef] [PubMed]
134. Noble, M.D.; Romac, J.; Vigna, S.R.; Liddle, R.A. A pH-sensitive,
neurogenic pathway mediates disease severity in a model of post-ERCP
pancreatitis. Gut 2008, 57, 1566–1571. [Google Scholar] [CrossRef]
[PubMed]
135. Romac, J.M.; Shahid, R.A.; Swain, S.M.; Vigna, S.R.; Liddle, R.A. Piezo1
is a mechanically activated ion channel and mediates pressure induced
pancreatitis. Nat. Commun. 2018, 9, 1715. [Google Scholar] [CrossRef]
[PubMed]
136. Venglovecz, V.; Rakonczay, Z., Jr.; Ozsvári, B.; Takács, T.; Lonovics, J.;
Varró, A.; Gray, M.A.; Argent, B.E.; Hegyi, P. Effects of bile acids on
pancreatic ductal bicarbonate secretion in guinea pig. Gut 2008, 57,
1102–1112. [Google Scholar] [CrossRef] [PubMed]
137. Vigna, S.R.; Shahid, R.A.; Nathan, J.D.; McVey, D.C.; Liddle, R.A.
Leukotriene B4 mediates inflammation via TRPV1 in duct obstruction-induced
pancreatitis in rats. Pancreas 2011, 40, 708–714. [Google Scholar]
[CrossRef] [PubMed]
138. Wen, L.; Javed, T.A.; Yimlamai, D.; Mukherjee, A.; Xiao, X.; Husain, S.Z.
Transient High Pressure in Pancreatic Ducts Promotes Inflammation and
Alters Tight Junctions via Calcineurin Signaling in Mice. Gastroenterology
2018, 155, 1250–1263.e5. [Google Scholar] [CrossRef] [PubMed]
139. Orabi, A.I.; Wen, L.; Javed, T.A.; Le, T.; Guo, P.; Sanker, S.; Ricks, D.;
Boggs, K.; Eisses, J.F.; Castro, C.; et al. Targeted inhibition of
pancreatic acinar cell calcineurin is a novel strategy to prevent
post-ERCP pancreatitis. Cell Mol. Gastroenterol. Hepatol. 2017, 3,
119–128. [Google Scholar] [CrossRef] [PubMed]
140. Maléth, J.; Venglovecz, V.; Rázga, Z.; Tiszlavicz, L.; Rakonczay, Z., Jr.;
Hegyi, P. Non-conjugated chenodeoxycholate induces severe mitochondrial
damage and inhibits bicarbonate transport in pancreatic duct cells. Gut
2011, 60, 136–138. [Google Scholar] [CrossRef]
141. Perides, G.; Laukkarinen, J.M.; Vassileva, G.; Steer, M.L. Biliary acute
pancreatitis in mice is mediated by the G-protein-coupled cell surface
bile acid receptor Gpbar1. Gastroenterology 2010, 138, 715–725. [Google
Scholar] [CrossRef] [PubMed]
142. Criddle, D.N.; McLaughlin, E.; Murphy, J.A.; Petersen, O.H.; Sutton, R.
The pancreas misled: Signals to pancreatitis. Pancreatology 2007, 7,
436–446. [Google Scholar] [CrossRef] [PubMed]
143. Li, Z.; Xu, C.; Tao, Y.; Liang, Y.; Liang, Q.; Li, J.; Li, R.; Ye, H.
Anisodamine alleviates lipopolysaccharide-induced pancreatic acinar cell
injury through NLRP3 inflammasome and NF-κB signaling pathway. J. Recept.
Signal Transduct. Res. 2020, 40, 58–66. [Google Scholar] [CrossRef]
[PubMed]
144. Pu, W.L.; Bai, R.Y.; Zhou, K.; Peng, Y.F.; Zhang, M.Y.; Hottiger, M.O.;
Li, W.H.; Gao, X.M.; Sun, L.K. Baicalein attenuates pancreatic
inflammatory injury through regulating MAPK, STAT 3 and NF-κB activation.
Int. Immunopharmacol. 2019, 72, 204–210. [Google Scholar] [CrossRef]
[PubMed]
145. Maléth, J.; Hegyi, P. Ca2+ toxicity and mitochondrial damage in acute
pancreatitis: Translational overview. Philos. Trans. R. Soc. Lond. B Biol.
Sci. 2016, 371, 20150425. [Google Scholar] [CrossRef] [PubMed]
146. Feng, S.; Wei, Q.; Hu, Q.; Huang, X.; Zhou, X.; Luo, G.; Deng, M.; Lü, M.
Research Progress on the Relationship Between Acute Pancreatitis and
Calcium Overload in Acinar Cells. Dig. Dis. Sci. 2019, 64, 25–38. [Google
Scholar] [CrossRef] [PubMed]
147. Carreras-Sureda, A.; Pihán, P.; Hetz, C. Calcium signaling at the
endoplasmic reticulum: Fine-tuning stress responses. Cell Calcium. 2018,
70, 24–31. [Google Scholar] [CrossRef] [PubMed]
148. Gerasimenko, J.V.; Gryshchenko, O.; Ferdek, P.E.; Stapleton, E.; Hébert,
T.O.; Bychkova, S.; Peng, S.; Begg, M.; Gerasimenko, O.V.; Petersen, O.H.
Ca2+ release-activated Ca2+ channel blockade as a potential tool in
antipancreatitis therapy. Proc. Natl. Acad. Sci. USA 2013, 110,
13186–13191. [Google Scholar] [CrossRef]
149. Zhang, S.L.; Yu, Y.; Roos, J.; Kozak, J.A.; Deerinck, T.J.; Ellisman,
M.H.; Stauderman, K.A.; Cahalan, M.D. STIM1 is a Ca2+ sensor that
activates CRAC channels and migrates from the Ca2+ store to the plasma
membrane. Nature 2005, 437, 902–905. [Google Scholar] [CrossRef]
150. Gukovskaya, A.S.; Pandol, S.J.; Gukovsky, I. New insights into the
pathways initiating and driving pancreatitis. Curr. Opin. Gastroenterol.
2016, 32, 429–435. [Google Scholar] [CrossRef]
151. Lur, G.; Sherwood, M.W.; Ebisui, E.; Haynes, L.; Feske, S.; Sutton, R.;
Burgoyne, R.D.; Mikoshiba, K.; Petersen, O.H.; Tepikin, A.V. InsP3
receptors and Orai channels in pancreatic acinar cells: Co-localization
and its consequences. Biochem. J. 2011, 436, 231–239. [Google Scholar]
[CrossRef] [PubMed]
152. Mukherjee, R.; Mareninova, O.A.; Odinokova, I.V.; Huang, W.; Murphy, J.;
Chvanov, M.; Javed, M.A.; Wen, L.; Booth, D.M.; Cane, M.C.; et al.
Mechanism of mitochondrial permeability transition pore induction and
damage in the pancreas: Inhibition prevents acute pancreatitis by
protecting production of ATP. Gut 2016, 65, 1333–1346. [Google Scholar]
[CrossRef] [PubMed]
153. Elmunzer, B.J.; Serrano, J.; Chak, A.; Edmundowicz, S.A.; Papachristou,
G.I.; Scheiman, J.M.; Singh, V.K.; Varadarajulu, S.; Vargo, J.J.;
Willingham, F.F.; et al. Rectal indomethacin alone versus indomethacin and
prophylactic pancreatic stent placement for preventing pancreatitis after
ERCP: Study protocol for a randomized controlled trial. Trials. 2016, 17,
120. [Google Scholar] [CrossRef] [PubMed]
154. Shalbueva, N.; Mareninova, O.A.; Gerloff, A.; Yuan, J.; Waldron, R.T.;
Pandol, S.J.; Gukovskaya, A.S. Effects of oxidative alcohol metabolism on
the mitochondrial permeability transition pore and necrosis in a mouse
model of alcoholic pancreatitis. Gastroenterology 2013, 144, 437–446.e6.
[Google Scholar] [CrossRef] [PubMed]
155. Gukovsky, I.; Pandol, S.J.; Gukovskaya, A.S. Organellar dysfunction in the
pathogenesis of pancreatitis. Antioxid. Redox Signal. 2011, 15, 2699–2710.
[Google Scholar] [CrossRef] [PubMed]
156. Odinokova, I.V.; Sung, K.F.; Mareninova, O.A.; Hermann, K.; Evtodienko,
Y.; Andreyev, A.; Gukovsky, I.; Gukovskaya, A.S. Mechanisms regulating
cytochrome c release in pancreatic mitochondria. Gut 2009, 58, 431–442.
[Google Scholar] [CrossRef] [PubMed]
157. Kroemer, G.; Galluzzi, L.; Brenner, C. Mitochondrial membrane
permeabilization in cell death. Physiol. Rev. 2007, 87, 99–163. [Google
Scholar] [CrossRef] [PubMed]
158. Baines, C.P.; Gutiérrez-Aguilar, M. The still uncertain identity of the
channel-forming unit(s) of the mitochondrial permeability transition pore.
Cell Calcium. 2018, 73, 121–130. [Google Scholar] [CrossRef] [PubMed]
159. Bernardi, P.; Rasola, A.; Forte, M.; Lippe, G. The Mitochondrial
Permeability Transition Pore: Channel Formation by F-ATP Synthase,
Integration in Signal Transduction, and Role in Pathophysiology. Physiol.
Rev. 2015, 95, 1111–1155. [Google Scholar] [CrossRef] [PubMed]
160. Lee, H.; Yoon, Y. Mitochondrial fission and fusion. Biochem. Soc. Trans.
2016, 44, 1725–1735. [Google Scholar] [CrossRef] [PubMed]
161. Gukovskaya, A.S.; Gukovsky, I. Which way to die: The regulation of acinar
cell death in pancreatitis by mitochondria, calcium, and reactive oxygen
species. Gastroenterology 2011, 140, 1876–1880. [Google Scholar]
[CrossRef] [PubMed]
162. Haanes, K.A.; Novak, I. ATP storage and uptake by isolated pancreatic
zymogen granules. Biochem. J. 2010, 429, 303–311. [Google Scholar]
[CrossRef] [PubMed]
163. Burgoyne, R.D.; Morgan, A. Secretory granule exocytosis. Physiol. Rev.
2003, 83, 581–632. [Google Scholar] [CrossRef] [PubMed]
164. Voronina, S.G.; Barrow, S.L.; Simpson, A.W.; Gerasimenko, O.V.; da Silva
Xavier, G.; Rutter, G.A.; Petersen, O.H.; Tepikin, A.V. Dynamic changes in
cytosolic and mitochondrial ATP levels in pancreatic acinar cells.
Gastroenterology 2010, 138, 1976–1987. [Google Scholar] [CrossRef]
[PubMed]
165. Chvanov, M.; De Faveri, F.; Moore, D.; Sherwood, M.W.; Awais, M.;
Voronina, S.; Sutton, R.; Criddle, D.N.; Haynes, L.; Tepikin, A.V.
Intracellular rupture, exocytosis and actin interaction of endocytic
vacuoles in pancreatic acinar cells: Initiating events in acute
pancreatitis. J. Physiol. 2018, 596, 2547–2564. [Google Scholar]
[CrossRef] [PubMed]
166. de Brito, O.M.; Scorrano, L. An intimate liaison: Spatial organization of
the endoplasmic reticulum-mitochondria relationship. EMBO J. 2010, 29,
2715–2723. [Google Scholar] [CrossRef] [PubMed]
167. Hayashi, T.; Rizzuto, R.; Hajnoczky, G.; Su, T.P. MAM: More than just a
housekeeper. Trends Cell Biol. 2009, 19, 81–88. [Google Scholar]
[CrossRef] [PubMed]
168. Cárdenas, C.; Miller, R.A.; Smith, I.; Bui, T.; Molgó, J.; Müller, M.;
Vais, H.; Cheung, K.H.; Yang, J.; Parker, I.; et al. Essential regulation
of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to
mitochondria. Cell 2010, 142, 270–283. [Google Scholar] [CrossRef]
[PubMed]
169. De Smedt, H.; Verkhratsky, A.; Muallem, S. Ca(2+) signaling mechanisms of
cell survival and cell death: An introduction. Cell Calcium. 2011, 50,
207–210. [Google Scholar] [CrossRef] [PubMed]
170. Ron, D.; Walter, P. Signal integration in the endoplasmic reticulum
unfolded protein response. Nat. Rev. Mol. Cell Biol. 2007, 8, 519–529.
[Google Scholar] [CrossRef] [PubMed]
171. Wu, J.S.; Li, W.M.; Chen, Y.N.; Zhao, Q.; Chen, Q.F. Endoplasmic reticulum
stress is activated in acute pancreatitis. J. Dig. Dis. 2016, 17, 295–303.
[Google Scholar] [CrossRef] [PubMed]
172. Lugea, A.; Gerloff, A.; Su, H.Y.; Xu, Z.; Go, A.; Hu, C.; French, S.W.;
Wilson, J.S.; Apte, M.V.; Waldron, R.T.; et al. The Combination of Alcohol
and Cigarette Smoke Induces Endoplasmic Reticulum Stress and Cell Death in
Pancreatic Acinar Cells. Gastroenterology 2017, 153, 1674–1686. [Google
Scholar] [CrossRef]
173. Hetz, C.; Chevet, E.; Oakes, S.A. Proteostasis control by the unfolded
protein response. Nat. Cell Biol. 2015, 17, 829–838. [Google Scholar]
[CrossRef] [PubMed]
174. Zhao, Q.; Tang, X.; Huang, J.; Li, J.; Chen, Q.; Sun, Y.; Wu, J. Melatonin
Attenuates Endoplasmic Reticulum Stress in Acute Pancreatitis. Pancreas
2018, 47, 884–891. [Google Scholar] [CrossRef] [PubMed]
175. Lugea, A.; Tischler, D.; Nguyen, J.; Gong, J.; Gukovsky, I.; French, S.W.;
Gorelick, F.S.; Pandol, S.J. Adaptive unfolded protein response attenuates
alcohol-induced pancreatic damage. Gastroenterology 2011, 140, 987–997.
[Google Scholar] [CrossRef]
176. Barrera, K.; Stanek, A.; Okochi, K.; Niewiadomska, Z.; Mueller, C.; Ou,
P.; John, D.; Alfonso, A.E.; Tenner, S.; Huan, C. Acinar cell injury
induced by inadequate unfolded protein response in acute pancreatitis.
World J. Gastrointest. Pathophysiol. 2018, 9, 37–46. [Google Scholar]
[CrossRef] [PubMed]
177. Kim, I.; Xu, W.; Reed, J.C. Cell death and endoplasmic reticulum stress:
Disease relevance and therapeutic opportunities. Nat. Rev. Drug Discov.
2008, 7, 1013–1030. [Google Scholar] [CrossRef] [PubMed]
178. Antonucci, L.; Fagman, J.B.; Kim, J.Y.; Todoric, J.; Gukovsky, I.; Mackey,
M.; Ellisman, M.H.; Karin, M. Basal autophagy maintains pancreatic acinar
cell homeostasis and protein synthesis and prevents ER stress. Proc. Natl.
Acad. Sci. USA 2015, 112, E6166–E6174. [Google Scholar] [CrossRef]
[PubMed]
179. Gukovskaya, A.S.; Gukovsky, I.; Algül, H.; Habtezion, A. Autophagy,
Inflammation, and Immune Dysfunction in the Pathogenesis of Pancreatitis.
Gastroenterology 2017, 153, 1212–1226. [Google Scholar] [CrossRef]
[PubMed]
180. Richardson, C.E.; Kooistra, T.; Kim, D.H. An essential role for XBP-1 in
host protection against immune activation in C. elegans. Nature 2010, 463,
1092–1095. [Google Scholar] [CrossRef] [PubMed]
181. Aoi, K.; Nishio, A.; Okazaki, T.; Takeo, M.; Masuda, M.; Fukui, T.;
Uchida, K.; Okazaki, K. Inhibition of the dephosphorylation of eukaryotic
initiation factor 2α ameliorates murine experimental pancreatitis.
Pancreatology 2019, 19, 548–556. [Google Scholar] [CrossRef] [PubMed]
182. Kapuy, O.; Márton, M.; Bánhegyi, G.; Vinod, P.K. Multiple system-level
feedback loops control life-and-death decisions in endoplasmic reticulum
stress. FEBS Lett. 2020, 594, 1112–1123. [Google Scholar] [CrossRef]
[PubMed]
183. Xu, C.; Bailly-Maitre, B.; Reed, J.C. Endoplasmic reticulum stress: Cell
life and death decisions. J. Clin. Investig. 2005, 115, 2656–2664. [Google
Scholar] [CrossRef] [PubMed]
184. Jin, H.Z.; Yang, X.J.; Zhao, K.L.; Mei, F.C.; Zhou, Y.; You, Y.D.; Wang,
W.X. Apocynin alleviates lung injury by suppressing NLRP3 inflammasome
activation and NF-κB signaling in acute pancreatitis. Int.
Immunopharmacol. 2019, 75, 105821. [Google Scholar] [CrossRef] [PubMed]
185. Chen, J.C.; Wu, M.L.; Huang, K.C.; Lin, W.W. HMG-CoA reductase inhibitors
activate the unfolded protein response and induce cytoprotective GRP78
expression. Cardiovasc. Res. 2008, 80, 138–150. [Google Scholar]
[CrossRef] [PubMed]
186. Lee, P.J.; Modha, K.; Chua, T.; Chak, A.; Jang, D.; Lopez, R.; Gougol, A.;
Papachristou, G.I.; Stevens, T. Association of Statins With Decreased
Acute Pancreatitis Severity: A Propensity Score Analysis. J. Clin.
Gastroenterol. 2018, 52, 742–746. [Google Scholar] [CrossRef] [PubMed]
187. Chiari, H. Über die Selbstverdauung des menschlichen Pankreas. Zeitschrift
für Heilkunde 1896, 17, 69–96. [Google Scholar]
188. Dawra, R.; Sah, R.P.; Dudeja, V.; Rishi, L.; Talukdar, R.; Garg, P.;
Saluja, A.K. Intra-acinar trypsinogen activation mediates early stages of
pancreatic injury but not inflammation in mice with acute pancreatitis.
Gastroenterology 2011, 141, 2210–2217.e2. [Google Scholar] [CrossRef]
[PubMed]
189. Talukdar, R.; Sareen, A.; Zhu, H.; Yuan, Z.; Dixit, A.; Cheema, H.;
George, J.; Barlass, U.; Sah, R.; Garg, S.K.; et al. Release of Cathepsin
B in Cytosol Causes Cell Death in Acute Pancreatitis. Gastroenterology
2016, 151, 747–758.e5. [Google Scholar] [CrossRef] [PubMed]
190. Liu, Y.; Liu, T.; Lei, T.; Zhang, D.; Du, S.; Girani, L.; Qi, D.; Lin, C.;
Tong, R.; Wang, Y. RIP1/RIP3-regulated necroptosis as a target for
multifaceted disease therapy (Review). Int. J. Mol. Med. 2019, 44,
771–786. [Google Scholar] [CrossRef] [PubMed]
191. Louhimo, J.; Steer, M.L.; Perides, G. Necroptosis Is an Important Severity
Determinant and Potential Therapeutic Target in Experimental Severe
Pancreatitis. Cell Mol. Gastroenterol. Hepatol. 2016, 2, 519–535. [Google
Scholar] [CrossRef] [PubMed]
192. Han, J.; Zhong, C.Q.; Zhang, D.W. Programmed necrosis: Backup to and
competitor with apoptosis in the immune system. Nat. Immunol. 2011, 12,
1143–1149. [Google Scholar] [CrossRef] [PubMed]
193. He, S.; Wang, L.; Miao, L.; Wang, T.; Du, F.; Zhao, L.; Wang, X. Receptor
interacting protein kinase-3 determines cellular necrotic response to
TNF-alpha. Cell. 2009, 137, 1100–1111. [Google Scholar] [CrossRef]
[PubMed]
194. Wang, G.; Qu, F.Z.; Li, L.; Lv, J.C.; Sun, B. Necroptosis: A potential,
promising target and switch in acute pancreatitis. Apoptosis. 2016, 21,
121–129. [Google Scholar] [CrossRef] [PubMed]
195. Harris, P.A.; Berger, S.B.; Jeong, J.U.; Nagilla, R.; Bandyopadhyay, D.;
Campobasso, N.; Capriotti, C.A.; Cox, J.A.; Dare, L.; Dong, X.; et al.
Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase
Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory
Diseases. J. Med. Chem. 2017, 60, 1247–1261. [Google Scholar] [CrossRef]
[PubMed]
196. Ren, Y.; Su, Y.; Sun, L.; He, S.; Meng, L.; Liao, D.; Liu, X.; Ma, Y.;
Liu, C.; Li, S.; et al. Discovery of a Highly Potent, Selective, and
Metabolically Stable Inhibitor of Receptor-Interacting Protein 1 (RIP1)
for the Treatment of Systemic Inflammatory Response Syndrome. J. Med.
Chem. 2017, 60, 972–986. [Google Scholar] [CrossRef] [PubMed]
197. Zhan, X.; Wan, J.; Zhang, G.; Song, L.; Gui, F.; Zhang, Y.; Li, Y.; Guo,
J.; Dawra, R.K.; Saluja, A.K.; et al. Elevated intracellular trypsin
exacerbates acute pancreatitis and chronic pancreatitis in mice. Am. J.
Physiol. Gastrointest. Liver Physiol. 2019, 316, G816–G825. [Google
Scholar] [CrossRef] [PubMed]
198. Sendler, M.; Weiss, F.U.; Golchert, J.; Homuth, G.; van den Brandt, C.;
Mahajan, U.M.; Partecke, L.I.; Döring, P.; Gukovsky, I.; Gukovskaya, A.S.;
et al. Cathepsin B-Mediated Activation of Trypsinogen in Endocytosing
Macrophages Increases Severity of Pancreatitis in Mice. Gastroenterology
2018, 154, 704–718.e10. [Google Scholar] [CrossRef] [PubMed]
199. Gea-Sorlí, S.; Closa, D. Role of macrophages in the progression of acute
pancreatitis. World J. Gastrointest. Pharmacol. Ther. 2010, 1, 107–111.
[Google Scholar] [CrossRef]
200. Aghdassi, A.A.; John, D.S.; Sendler, M.; Weiss, F.U.; Reinheckel, T.;
Mayerle, J.; Lerch, M.M. Cathepsin D regulates cathepsin B activation and
disease severity predominantly in inflammatory cells during experimental
pancreatitis. J. Biol. Chem. 2018, 293, 1018–1029. [Google Scholar]
[CrossRef] [PubMed]
201. Whitcomb, D.C.; Gorry, M.C.; Preston, R.A.; Furey, W.; Sossenheimer, M.J.;
Ulrich, C.D.; Martin, S.P.; Gates, L.K., Jr.; Amann, S.T.; Toskes, P.P.;
et al. Hereditary pancreatitis is caused by a mutation in the cationic
trypsinogen gene. Nat. Genet. 1996, 14, 141–145. [Google Scholar]
[CrossRef] [PubMed]
202. Nguyen, T.D.; Moody, M.W.; Steinhoff, M.; Okolo, C.; Koh, D.S.; Bunnett,
N.W. Trypsin activates pancreatic duct epithelial cell ion channels
through proteinase-activated receptor-2. J. Clin. Investig. 1999, 103,
261–269. [Google Scholar] [CrossRef] [PubMed]
203. Alvarez, C.; Regan, J.P.; Merianos, D.; Bass, B.L. Protease-activated
receptor-2 regulates bicarbonate secretion by pancreatic duct cells in
vitro. Surgery 2004, 136, 669–676. [Google Scholar] [CrossRef] [PubMed]
204. Laukkarinen, J.M.; Weiss, E.R.; van Acker, G.J.; Steer, M.L.; Perides, G.
Protease-activated receptor-2 exerts contrasting model-specific effects on
acute experimental pancreatitis. J. Biol. Chem. 2008, 283, 20703–20712.
[Google Scholar] [CrossRef] [PubMed]
205. Namkung, W.; Han, W.; Luo, X.; Muallem, S.; Cho, K.H.; Kim, K.H.; Lee,
M.G. Protease-activated receptor 2 exerts local protection and mediates
some systemic complications in acute pancreatitis. Gastroenterology 2004,
126, 1844–1859. [Google Scholar] [CrossRef] [PubMed]
206. Sharma, A.; Tao, X.; Gopal, A.; Ligon, B.; Andrade-Gordon, P.; Steer,
M.L.; Perides, G. Protection against acute pancreatitis by activation of
protease-activated receptor-2. Am. J. Physiol. Gastrointest. Liver
Physiol. 2005, 288, G388–G395. [Google Scholar] [CrossRef] [PubMed]
207. Gaiser, S.; Daniluk, J.; Liu, Y.; Tsou, L.; Chu, J.; Lee, W.; Longnecker,
D.S.; Logsdon, C.D.; Ji, B. Intracellular activation of trypsinogen in
transgenic mice induces acute but not chronic pancreatitis. Gut 2011, 60,
1379–1388. [Google Scholar] [CrossRef] [PubMed]
208. Nikam, A.; Dawra, R.; Saluja, A.; Dudeja, V. Pancreatitis: A Tale of Two
Proteases. Gastroenterology 2018, 154, 482–484. [Google Scholar]
[CrossRef] [PubMed]
209. Sah, R.P.; Dudeja, V.; Dawra, R.K.; Saluja, A.K. Cerulein-induced chronic
pancreatitis does not require intra-acinar activation of trypsinogen in
mice. Gastroenterology 2013, 144, 1076–1085.e2. [Google Scholar]
[CrossRef] [PubMed]
210. Gukovsky, I.; Gukovskaya, A.S.; Blinman, T.A.; Zaninovic, V.; Pandol, S.J.
Early NF-kappaB activation is associated with hormone-induced
pancreatitis. Am. J. Physiol. 1998, 275, G1402–G1414. [Google Scholar]
[CrossRef] [PubMed]
211. Steinle, A.U.; Weidenbach, H.; Wagner, M.; Adler, G.; Schmid, R.M.
NF-kappaB/Rel activation in cerulein pancreatitis. Gastroenterology 1999,
116, 420–430. [Google Scholar] [CrossRef] [PubMed]
212. Krüger, B.; Albrecht, E.; Lerch, M.M. The role of intracellular calcium
signaling in premature protease activation and the onset of pancreatitis.
Am. J. Pathol. 2000, 157, 43–50. [Google Scholar] [CrossRef] [PubMed]
213. Han, B.; Logsdon, C.D. CCK stimulates mob-1 expression and NF-kappaB
activation via protein kinase C and intracellular Ca(2+). Am. J. Physiol.
Cell Physiol. 2000, 278, C344–C351. [Google Scholar] [CrossRef] [PubMed]
214. Neuhöfer, P.; Liang, S.; Einwächter, H.; Schwerdtfeger, C.; Wartmann, T.;
Treiber, M.; Zhang, H.; Schulz, H.U.; Dlubatz, K.; Lesina, M.; et al.
Deletion of IκBα activates RelA to reduce acute pancreatitis in mice
through up-regulation of Spi2A. Gastroenterology 2013, 144, 192–201.
[Google Scholar] [CrossRef] [PubMed]
215. Rakonczay, Z., Jr.; Hegyi, P.; Takács, T.; McCarroll, J.; Saluja, A.K. The
role of NF-kappaB activation in the pathogenesis of acute pancreatitis.
Gut 2008, 57, 259–267. [Google Scholar] [CrossRef] [PubMed]
216. Koike, Y.; Kanai, T.; Saeki, K.; Nakamura, Y.; Nakano, M.; Mikami, Y.;
Yamagishi, Y.; Nakamoto, N.; Ebinuma, H.; Hibi, T. MyD88-dependent
interleukin-10 production from regulatory CD11b⁺Gr-1(high) cells
suppresses development of acute cerulein pancreatitis in mice. Immunol.
Lett. 2012, 148, 172–177. [Google Scholar] [CrossRef] [PubMed]
217. Aleksic, T.; Baumann, B.; Wagner, M.; Adler, G.; Wirth, T.; Weber, C.K.
Cellular immune reaction in the pancreas is induced by constitutively
active IkappaB kinase-2. Gut 2007, 56, 227–236. [Google Scholar]
[CrossRef] [PubMed]
218. Cobo, I.; Martinelli, P.; Flández, M.; Bakiri, L.; Zhang, M.;
Carrillo-de-Santa-Pau, E.; Jia, J.; Sánchez-Arévalo Lobo, V.J.; Megías,
D.; Felipe, I.; et al. Transcriptional regulation by NR5A2 links
differentiation and inflammation in the pancreas. Nature 2018, 554,
533–537. [Google Scholar] [CrossRef] [PubMed]
219. Guo, L.; Sans, M.D.; Hou, Y.; Ernst, S.A.; Williams, J.A. c-Jun/AP-1 is
required for CCK-induced pancreatic acinar cell dedifferentiation and DNA
synthesis in vitro. Am. J. Physiol. Gastrointest. Liver Physiol. 2012,
302, G1381–G1396. [Google Scholar] [CrossRef] [PubMed]
220. Gukovskaya, A.S.; Mouria, M.; Gukovsky, I.; Reyes, C.N.; Kasho, V.N.;
Faller, L.D.; Pandol, S.J. Ethanol metabolism and transcription factor
activation in pancreatic acinar cells in rats. Gastroenterology 2002, 122,
106–118. [Google Scholar] [CrossRef]
221. Jakkampudi, A.; Jangala, R.; Reddy, B.R.; Mitnala, S.; Nageshwar Reddy,
D.; Talukdar, R. NF-κB in acute pancreatitis: Mechanisms and therapeutic
potential. Pancreatology 2016, 16, 477–488. [Google Scholar] [CrossRef]
[PubMed]
222. Galluzzi, L.; Vitale, I.; Aaronson, S.A.; Abrams, J.M.; Adam, D.;
Agostinis, P.; Alnemri, E.S.; Altucci, L.; Amelio, I.; Andrews, D.W.; et
al. Molecular mechanisms of cell death: Recommendations of the
Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018, 25,
486–541. [Google Scholar] [CrossRef] [PubMed]
223. Gaman, L.; Dragos, D.; Vlad, A.; Robu, G.C.; Radoi, M.P.; Stroica, L.;
Badea, M.; Gilca, M. Phytoceuticals in Acute Pancreatitis: Targeting the
Balance between Apoptosis and Necrosis. Evid. Based Complement Alternat.
Med. 2018, 2018, 5264592. [Google Scholar] [CrossRef] [PubMed]
224. Lee, B.; Zhao, Q.; Habtezion, A. Immunology of pancreatitis and
environmental factors. Curr. Opin. Gastroenterol. 2017, 33, 383–389.
[Google Scholar] [CrossRef] [PubMed]
225. Hutchins, A.P.; Diez, D.; Miranda-Saavedra, D. The IL-10/STAT3-mediated
anti-inflammatory response: Recent developments and future challenges.
Brief Funct. Genomics. 2013, 12, 489–498. [Google Scholar] [CrossRef]
[PubMed]
226. Lin, R.; Chen, F.; Wen, S.; Teng, T.; Pan, Y.; Huang, H. Interleukin-10
attenuates impairment of the blood-brain barrier in a severe acute
pancreatitis rat model. J. Inflamm. 2018, 15, 4. [Google Scholar]
[CrossRef] [PubMed]
227. Warzecha, Z.; Dembinski, A.; Ceranowicz, P.; Konturek, S.J.; Tomaszewska,
R.; Stachura, J.; Konturek, P.C. IGF-1 stimulates production of
interleukin-10 and inhibits development of caerulein-induced pancreatitis.
J. Physiol. Pharmacol. 2003, 54, 575–590. [Google Scholar] [PubMed]
228. Sharma, D.; Jakkampudi, A.; Reddy, R.; Reddy, P.B.; Patil, A.; Murthy,
H.V.V.; Rao, G.V.; Reddy, D.N.; Talukdar, R. Association of Systemic
Inflammatory and Anti-inflammatory Responses with Adverse Outcomes in
Acute Pancreatitis: Preliminary Results of an Ongoing Study. Dig. Dis.
Sci. 2017, 62, 3468–3478. [Google Scholar] [CrossRef] [PubMed]
229. Sendler, M.; van den Brandt, C.; Glaubitz, J.; Wilden, A.; Golchert, J.;
Weiss, F.U.; Homuth, G.; De Freitas Chama, L.L.; Mishra, N.; Mahajan,
U.M.; et al. NLRP3 Inflammasome Regulates Development of Systemic
Inflammatory Response and Compensatory Anti-Inflammatory Response
Syndromes in Mice With Acute Pancreatitis. Gastroenterology 2020, 158,
253–269.e14. [Google Scholar] [CrossRef] [PubMed]
230. Ahmad, A.; Haas De Mello, A.; Szczesny, B.; Törö, G.; Marcatti, M.;
Druzhyna, N.; Liaudet, L.; Tarantini, S.; Salomao, R.; Garcia Soriano, F.;
et al. Effects of the Poly(ADP-Ribose) Polymerase Inhibitor Olaparib in
Cerulein-Induced Pancreatitis. Shock 2020, 53, 653–665. [Google Scholar]
[CrossRef]
231. Gregorić, P.; Doklestić, K.; Stanković, S.; Sijacki, A.; Karamarković, A.;
Radenković, D.; Ivancević, N.; Bajec, D. Interleukin-12 as a predictor of
outcome in patients with severe acute pancreatitis. Hepatogastroenterology
2014, 61, 208–211. [Google Scholar] [PubMed]
232. Iyer, S.; Bawa, E.P.; Tarique, M.; Dudeja, V. Know Thy Enemy-Understanding
the Role of Inflammation in Severe Acute Pancreatitis. Gastroenterology
2020, 158, 46–48. [Google Scholar] [CrossRef] [PubMed]
233. Oppenheim, J.J.; Yang, D. Alarmins: Chemotactic activators of immune
responses. Curr. Opin. Immunol. 2005, 17, 359–365. [Google Scholar]
[CrossRef] [PubMed]
234. Ferrero-Andrés, A.; Panisello-Roselló, A.; Roselló-Catafau, J.; Folch-Puy,
E. NLRP3 Inflammasome-Mediated Inflammation in Acute Pancreatitis. Int. J.
Mol. Sci. 2020, 21, 5386. [Google Scholar] [CrossRef] [PubMed]
235. Kocsis, A.K.; Szabolcs, A.; Hofner, P.; Takács, T.; Farkas, G.; Boda, K.;
Mándi, Y. Plasma concentrations of high-mobility group box protein 1,
soluble receptor for advanced glycation end-products and circulating DNA
in patients with acute pancreatitis. Pancreatology 2009, 9, 383–391.
[Google Scholar] [CrossRef] [PubMed]
236. Lindström, O.; Tukiainen, E.; Kylänpää, L.; Mentula, P.; Rouhiainen, A.;
Puolakkainen, P.; Rauvala, H.; Repo, H. Circulating levels of a soluble
form of receptor for advanced glycation end products and high-mobility
group box chromosomal protein 1 in patients with acute pancreatitis.
Pancreas 2009, 38, e215–e220. [Google Scholar] [CrossRef] [PubMed]
237. Yasuda, T.; Ueda, T.; Shinzeki, M.; Sawa, H.; Nakajima, T.; Takeyama, Y.;
Kuroda, Y. Increase of high-mobility group box chromosomal protein 1 in
blood and injured organs in experimental severe acute pancreatitis.
Pancreas 2007, 34, 487–488. [Google Scholar] [CrossRef] [PubMed]
238. Sawa, H.; Ueda, T.; Takeyama, Y.; Yasuda, T.; Shinzeki, M.; Nakajima, T.;
Kuroda, Y. Blockade of high mobility group box-1 protein attenuates
experimental severe acute pancreatitis. World J. Gastroenterol. 2006, 12,
7666–7670. [Google Scholar] [CrossRef] [PubMed]
239. Luan, Z.G.; Zhang, X.J.; Yin, X.H.; Ma, X.C.; Zhang, H.; Zhang, C.; Guo,
R.X. Downregulation of HMGB1 protects against the development of acute
lung injury after severe acute pancreatitis. Immunobiology 2013, 218,
1261–1270. [Google Scholar] [CrossRef] [PubMed]
240. Yuan, H.; Jin, X.; Sun, J.; Li, F.; Feng, Q.; Zhang, C.; Cao, Y.; Wang, Y.
Protective effect of HMGB1 a box on organ injury of acute pancreatitis in
mice. Pancreas 2009, 38, 143–148. [Google Scholar] [CrossRef] [PubMed]
241. Zhang, Z.W.; Zhang, Q.Y.; Zhou, M.T.; Liu, N.X.; Chen, T.K.; Zhu, Y.F.;
Wu, L. Antioxidant inhibits HMGB1 expression and reduces pancreas injury
in rats with severe acute pancreatitis. Dig. Dis. Sci. 2010, 55,
2529–2536. [Google Scholar] [CrossRef] [PubMed]
242. Yang, Z.Y.; Ling, Y.; Yin, T.; Tao, J.; Xiong, J.X.; Wu, H.S.; Wang, C.Y.
Delayed ethyl pyruvate therapy attenuates experimental severe acute
pancreatitis via reduced serum high mobility group box 1 levels in rats.
World J. Gastroenterol. 2008, 14, 4546–4550. [Google Scholar] [CrossRef]
243. Zhao, Q.; Wei, Y.; Pandol, S.J.; Li, L.; Habtezion, A. STING Signaling
Promotes Inflammation in Experimental Acute Pancreatitis. Gastroenterology
2018, 154, 1822–1835.e2. [Google Scholar] [CrossRef] [PubMed]
244. Malmstrøm, M.L.; Hansen, M.B.; Andersen, A.M.; Ersbøll, A.K.; Nielsen,
O.H.; Jørgensen, L.N.; Novovic, S. Cytokines and organ failure in acute
pancreatitis: Inflammatory response in acute pancreatitis. Pancreas 2012,
41, 271–277. [Google Scholar] [CrossRef] [PubMed]
245. Guo, H.; Callaway, J.B.; Ting, J.P. Inflammasomes: Mechanism of action,
role in disease, and therapeutics. Nat. Med. 2015, 21, 677–687. [Google
Scholar] [CrossRef] [PubMed]
246. Hoque, R.; Sohail, M.; Malik, A.; Sarwar, S.; Luo, Y.; Shah, A.; Barrat,
F.; Flavell, R.; Gorelick, F.; Husain, S.; et al. TLR9 and the NLRP3
inflammasome link acinar cell death with inflammation in acute
pancreatitis. Gastroenterology 2011, 141, 358–369. [Google Scholar]
[CrossRef] [PubMed]
247. Fu, Q.; Zhai, Z.; Wang, Y.; Xu, L.; Jia, P.; Xia, P.; Liu, C.; Zhang, X.;
Qin, T.; Zhang, H. NLRP3 Deficiency Alleviates Severe Acute Pancreatitis
and Pancreatitis-Associated Lung Injury in a Mouse Model. Biomed. Res.
Int. 2018, 2018, 1294951. [Google Scholar] [CrossRef] [PubMed]
248. Hoque, R.; Farooq, A.; Ghani, A.; Gorelick, F.; Mehal, W.Z. Lactate
reduces liver and pancreatic injury in Toll-like receptor- and
inflammasome-mediated inflammation via GPR81-mediated suppression of
innate immunity. Gastroenterology 2014, 146, 1763–1774. [Google Scholar]
[CrossRef] [PubMed]
249. Wu, B.U.; Hwang, J.Q.; Gardner, T.H.; Repas, K.; Delee, R.; Yu, S.; Smith,
B.; Banks, P.A.; Conwell, D.L. Lactated Ringer’s solution reduces systemic
inflammation compared with saline in patients with acute pancreatitis.
Clin. Gastroenterol. Hepatol. 2011, 9, 710–717.e1. [Google Scholar]
[CrossRef] [PubMed]
250. de-Madaria, E.; Herrera-Marante, I.; González-Camacho, V.; Bonjoch, L.;
Quesada-Vázquez, N.; Almenta-Saavedra, I.; Miralles-Maciá, C.;
Acevedo-Piedra, N.G.; Roger-Ibáñez, M.; Sánchez-Marin, C.; et al. Fluid
resuscitation with lactated Ringer’s solution vs normal saline in acute
pancreatitis: A triple-blind, randomized, controlled trial. United Eur.
Gastroenterol. J. 2018, 6, 63–72. [Google Scholar] [CrossRef] [PubMed]
251. Shen, A.; Kim, H.J.; Oh, G.S.; Lee, S.B.; Lee, S.H.; Pandit, A.; Khadka,
D.; Choe, S.K.; Kwak, S.C.; Yang, S.H.; et al. NAD+ augmentation
ameliorates acute pancreatitis through regulation of inflammasome
signalling. Sci. Rep. 2017, 7, 3006. [Google Scholar] [CrossRef] [PubMed]
252. Xue, J.; Habtezion, A. Carbon monoxide-based therapy ameliorates acute
pancreatitis via TLR4 inhibition. J. Clin. Investig. 2014, 124, 437–447.
[Google Scholar] [CrossRef] [PubMed]
253. Wu, X.B.; Sun, H.Y.; Luo, Z.L.; Cheng, L.; Duan, X.M.; Ren, J.D.
Plasma-derived exosomes contribute to pancreatitis-associated lung injury
by triggering NLRP3-dependent pyroptosis in alveolar macrophages. Biochim.
Biophys. Acta Mol. Basis Dis. 2020, 1866, 165685. [Google Scholar]
[CrossRef] [PubMed]
254. Algaba-Chueca, F.; de-Madaria, E.; Lozano-Ruiz, B.; Martínez-Cardona, C.;
Quesada-Vázquez, N.; Bachiller, V.; Tarín, F.; Such, J.; Francés, R.;
Zapater, P.; et al. The expression and activation of the AIM2 inflammasome
correlates with inflammation and disease severity in patients with acute
pancreatitis. Pancreatology 2017, 17, 364–371. [Google Scholar] [CrossRef]
[PubMed]
255. Hartman, H.; Wetterholm, E.; Thorlacius, H.; Regnér, S. Histone
deacetylase regulates trypsin activation, inflammation, and tissue damage
in acute pancreatitis in mice. Dig. Dis. Sci. 2015, 60, 1284–1289. [Google
Scholar] [CrossRef] [PubMed]
256. He, J.; Ma, M.; Li, D.; Wang, K.; Wang, Q.; Li, Q.; He, H.; Zhou, Y.; Li,
Q.; Hou, X.; et al. Sulfiredoxin-1 attenuates injury and inflammation in
acute pancreatitis through the ROS/ER stress/Cathepsin B axis. Cell Death
Dis. 2021, 12, 626. [Google Scholar] [CrossRef] [PubMed]
257. Hoque, R.; Mehal, W.Z. Inflammasomes in pancreatic physiology and disease.
Am. J. Physiol. Gastrointest. Liver Physiol. 2015, 308, G643–G651. [Google
Scholar] [CrossRef] [PubMed]
258. Watanabe, T.; Kudo, M.; Strober, W. Immunopathogenesis of pancreatitis.
Mucosal. Immunol. 2017, 10, 283–298. [Google Scholar] [CrossRef] [PubMed]
259. Lugea, A.; Waldron, R.T.; Mareninova, O.A.; Shalbueva, N.; Deng, N.; Su,
H.Y.; Thomas, D.D.; Jones, E.K.; Messenger, S.W.; Yang, J.; et al. Human
Pancreatic Acinar Cells: Proteomic Characterization, Physiologic
Responses, and Organellar Disorders in ex Vivo Pancreatitis. Am. J.
Pathol. 2017, 187, 2726–2743. [Google Scholar] [CrossRef] [PubMed]
260. Griffith, J.W.; Sokol, C.L.; Luster, A.D. Chemokines and chemokine
receptors: Positioning cells for host defense and immunity. Annu. Rev.
Immunol. 2014, 32, 659–702. [Google Scholar] [CrossRef] [PubMed]
261. Zhou, G.X.; Zhu, X.J.; Ding, X.L.; Zhang, H.; Chen, J.P.; Qiang, H.;
Zhang, H.F.; Wei, Q. Protective effects of MCP-1 inhibitor on a rat model
of severe acute pancreatitis. Hepatobiliary Pancreat. Dis. Int. 2010, 9,
201–207. [Google Scholar] [PubMed]
262. Malla, S.R.; Kärrman Mårdh, C.; Günther, A.; Mahajan, U.M.; Sendler, M.;
D’Haese, J.; Weiss, F.U.; Lerch, M.M.; Hansen, M.B.; Mayerle, J. Effect of
oral administration of AZD8309, a CXCR2 antagonist, on the severity of
experimental pancreatitis. Pancreatology 2016, 16, 761–769. [Google
Scholar] [CrossRef] [PubMed]
263. Saeki, K.; Kanai, T.; Nakano, M.; Nakamura, Y.; Miyata, N.; Sujino, T.;
Yamagishi, Y.; Ebinuma, H.; Takaishi, H.; Ono, Y.; et al. CCL2-induced
migration and SOCS3-mediated activation of macrophages are involved in
cerulein-induced pancreatitis in mice. Gastroenterology 2012, 142,
1010–1020.e9. [Google Scholar] [CrossRef] [PubMed]
264. Papachristou, G.I. Prediction of severe acute pancreatitis: Current
knowledge and novel insights. World J. Gastroenterol. 2008, 14, 6273–6275.
[Google Scholar] [CrossRef] [PubMed]
265. Jakkampudi, A.; Jangala, R.; Reddy, R.; Mitnala, S.; Rao, G.V.; Pradeep,
R.; Reddy, D.N.; Talukdar, R. Acinar injury and early cytokine response in
human acute biliary pancreatitis. Sci. Rep. 2017, 7, 15276. [Google
Scholar] [CrossRef] [PubMed]
266. Ushio-Fukai, M. Compartmentalization of redox signaling through NADPH
oxidase-derived ROS. Antioxid. Redox Signal. 2009, 11, 1289–1299. [Google
Scholar] [CrossRef] [PubMed]
267. Sendler, M.; Dummer, A.; Weiss, F.U.; Krüger, B.; Wartmann, T.;
Scharffetter-Kochanek, K.; van Rooijen, N.; Malla, S.R.; Aghdassi, A.;
Halangk, W.; et al. Tumour necrosis factor α secretion induces protease
activation and acinar cell necrosis in acute experimental pancreatitis in
mice. Gut 2013, 62, 430–439. [Google Scholar] [CrossRef] [PubMed]
268. Gukovsky, I.; Li, N.; Todoric, J.; Gukovskaya, A.; Karin, M. Inflammation,
autophagy, and obesity: Common features in the pathogenesis of
pancreatitis and pancreatic cancer. Gastroenterology 2013, 144,
1199–1209.e4. [Google Scholar] [CrossRef]
269. Habtezion, A. Inflammation in acute and chronic pancreatitis. Curr. Opin.
Gastroenterol. 2015, 31, 395–399. [Google Scholar] [CrossRef] [PubMed]
270. Mareninova, O.A.; Sendler, M.; Malla, S.R.; Yakubov, I.; French, S.W.;
Tokhtaeva, E.; Vagin, O.; Oorschot, V.; Lüllmann-Rauch, R.; Blanz, J.; et
al. Lysosome associated membrane proteins maintain pancreatic acinar cell
homeostasis: LAMP-2 deficient mice develop pancreatitis. Cell Mol.
Gastroenterol. Hepatol. 2015, 1, 678–694. [Google Scholar] [CrossRef]
271. Diakopoulos, K.N.; Lesina, M.; Wörmann, S.; Song, L.; Aichler, M.; Schild,
L.; Artati, A.; Römisch-Margl, W.; Wartmann, T.; Fischer, R.; et al.
Impaired autophagy induces chronic atrophic pancreatitis in mice via sex-
and nutrition-dependent processes. Gastroenterology 2015, 148,
626–638.e17. [Google Scholar] [CrossRef] [PubMed]
272. Perides, G.; Weiss, E.R.; Michael, E.S.; Laukkarinen, J.M.; Duffield,
J.S.; Steer, M.L. TNF-alpha-dependent regulation of acute pancreatitis
severity by Ly-6C(hi) monocytes in mice. J. Biol. Chem. 2011, 286,
13327–13335. [Google Scholar] [CrossRef] [PubMed]
273. Fink, S.L.; Cookson, B.T. Caspase-1-dependent pore formation during
pyroptosis leads to osmotic lysis of infected host macrophages. Cell
Microbiol. 2006, 8, 1812–1825. [Google Scholar] [CrossRef] [PubMed]
274. Bergsbaken, T.; Fink, S.L.; Cookson, B.T. Pyroptosis: Host cell death and
inflammation. Nat. Rev. Microbiol. 2009, 7, 99–109. [Google Scholar]
[CrossRef] [PubMed]
275. Pan, B.; Li, Y.; Liu, Y.; Wang, W.; Huang, G.; Ouyang, Y. Circulating
CitH3 Is a Reliable Diagnostic and Prognostic Biomarker of Septic Patients
in Acute Pancreatitis. Front. Immunol. 2021, 12, 766391. [Google Scholar]
[CrossRef] [PubMed]
276. Merza, M.; Hartman, H.; Rahman, M.; Hwaiz, R.; Zhang, E.; Renström, E.;
Luo, L.; Mörgelin, M.; Regner, S.; Thorlacius, H. Neutrophil Extracellular
Traps Induce Trypsin Activation, Inflammation, and Tissue Damage in Mice
With Severe Acute Pancreatitis. Gastroenterology 2015, 149, 1920–1931.e8.
[Google Scholar] [CrossRef]
277. Leppkes, M.; Schick, M.; Hohberger, B.; Mahajan, A.; Knopf, J.; Schett,
G.; Muñoz, L.E.; Herrmann, M. Updates on NET formation in health and
disease. Semin Arthritis Rheum. 2019, 49, S43–S48. [Google Scholar]
[CrossRef] [PubMed]
278. Cahilog, Z.; Zhao, H.; Wu, L.; Alam, A.; Eguchi, S.; Weng, H.; Ma, D. The
Role of Neutrophil NETosis in Organ Injury: Novel Inflammatory Cell Death
Mechanisms. Inflammation 2020, 43, 2021–2032. [Google Scholar] [CrossRef]
[PubMed]
279. Murthy, P.; Singhi, A.D.; Ross, M.A.; Loughran, P.; Paragomi, P.;
Papachristou, G.I.; Whitcomb, D.C.; Zureikat, A.H.; Lotze, M.T.; Zeh Iii,
H.J.; et al. Enhanced Neutrophil Extracellular Trap Formation in Acute
Pancreatitis Contributes to Disease Severity and Is Reduced by
Chloroquine. Front. Immunol. 2019, 10, 28. [Google Scholar] [CrossRef]
[PubMed]
280. Wan, J.; Ren, Y.; Yang, X.; Li, X.; Xia, L.; Lu, N. The Role of
Neutrophils and Neutrophil Extracellular Traps in Acute Pancreatitis.
Front. Cell Dev. Biol. 2021, 8, 565758. [Google Scholar] [CrossRef]
[PubMed]
281. Hu, J.; Kang, H.; Chen, H.; Yao, J.; Yi, X.; Tang, W.; Wan, M. Targeting
neutrophil extracellular traps in severe acute pancreatitis treatment.
Therap. Adv. Gastroenterol. 2020, 13, 1756284820974913. [Google Scholar]
[CrossRef] [PubMed]
282. Zhou, X.; Jin, S.; Pan, J.; Lin, Q.; Yang, S.; Ambe, P.C.; Basharat, Z.;
Zimmer, V.; Wang, W.; Hong, W. Damage associated molecular patterns and
neutrophil extracellular traps in acute pancreatitis. Front. Cell Infect.
Microbiol. 2022, 12, 927193. [Google Scholar] [CrossRef] [PubMed]
283. Mentula, P.; Kylänpää, M.L.; Kemppainen, E.; Jansson, S.E.; Sarna, S.;
Puolakkainen, P.; Haapiainen, R.; Repo, H. Plasma anti-inflammatory
cytokines and monocyte human leucocyte antigen-DR expression in patients
with acute pancreatitis. Scand J. Gastroenterol. 2004, 39, 178–187.
[Google Scholar] [CrossRef] [PubMed]
284. Zhang, R.; Shi, J.; Zhang, R.; Ni, J.; Habtezion, A.; Wang, X.; Hu, G.;
Xue, J. Expanded CD14hiCD16- Immunosuppressive Monocytes Predict Disease
Severity in Patients with Acute Pancreatitis. J. Immunol. 2019, 202,
2578–2584. [Google Scholar] [CrossRef] [PubMed]
285. Pan, T.; Zhou, T.; Li, L.; Liu, Z.; Chen, Y.; Mao, E.; Li, M.; Qu, H.;
Liu, J. Monocyte programmed death ligand-1 expression is an early marker
for predicting infectious complications in acute pancreatitis. Crit. Care
2017, 21, 186. [Google Scholar] [CrossRef] [PubMed]
286. Liu, H.; Li, W.; Wang, X.; Li, J.; Yu, W. Early gut mucosal dysfunction in
patients with acute pancreatitis. Pancreas 2008, 36, 192–196. [Google
Scholar] [CrossRef] [PubMed]
287. Rahman, S.H.; Ammori, B.J.; Holmfield, J.; Larvin, M.; McMahon, M.J.
Intestinal hypoperfusion contributes to gut barrier failure in severe
acute pancreatitis. J. Gastrointest. Surg. 2003, 7, 26–36. [Google
Scholar] [CrossRef] [PubMed]
288. Li, J.P.; Yang, J.; Huang, J.R.; Jiang, D.L.; Zhang, F.; Liu, M.F.; Qiang,
Y.; Gu, Y.L. Immunosuppression and the infection caused by gut mucosal
barrier dysfunction in patients with early severe acute pancreatitis.
Front. Biosci. 2013, 18, 892–900. [Google Scholar] [CrossRef]
289. Venkatesh, K.; Glenn, H.; Delaney, A.; Andersen, C.R.; Sasson, S.C. Fire
in the belly: A scoping review of the immunopathological mechanisms of
acute pancreatitis. Front. Immunol. 2023, 13, 1077414. [Google Scholar]
[CrossRef] [PubMed]
290. Bonjoch, L.; Casas, V.; Carrascal, M.; Closa, D. Involvement of exosomes
in lung inflammation associated with experimental acute pancreatitis. J.
Pathol. 2016, 240, 235–245. [Google Scholar] [CrossRef]
291. Yang, Y.; Huang, Q.; Luo, C.; Wen, Y.; Liu, R.; Sun, H.; Tang, L.
MicroRNAs in acute pancreatitis: From pathogenesis to novel diagnosis and
therapy. J. Cell Physiol. 2020, 235, 1948–1961. [Google Scholar]
[CrossRef] [PubMed]
292. Munir, F.; Jamshed, M.B.; Shahid, N.; Muhammad, S.A.; Ghanem, N.B.; Qiyu,
Z. Current status of diagnosis and Mesenchymal stem cells therapy for
acute pancreatitis. Physiol. Rep. 2019, 7, e14170. [Google Scholar]
[CrossRef] [PubMed]
293. Hasan, A.; Moscoso, D.I.; Kastrinos, F. The Role of Genetics in
Pancreatitis. Gastrointest. Endosc. Clin. N. Am. 2018, 28, 587–603.
[Google Scholar] [CrossRef] [PubMed]
294. Zator, Z.; Whitcomb, D.C. Insights into the genetic risk factors for the
development of pancreatic disease. Therap. Adv. Gastroenterol. 2017, 10,
323–336. [Google Scholar] [CrossRef] [PubMed]
295. van Geenen, E.J.; Smits, M.M.; Schreuder, T.C.; van der Peet, D.L.;
Bloemena, E.; Mulder, C.J. Smoking is related to pancreatic fibrosis in
humans. Am. J. Gastroenterol. 2011, 106, 1161–1166; quiz 1167. [Google
Scholar] [CrossRef] [PubMed]
296. Klöppel, G.; Maillet, B. Pseudocysts in chronic pancreatitis: A
morphological analysis of 57 resection specimens and 9 autopsy pancreata.
Pancreas 1991, 6, 266–274. [Google Scholar] [CrossRef] [PubMed]
297. Klöppel, G.; Maillet, B. The morphological basis for the evolution of
acute pancreatitis into chronic pancreatitis. Virchows Arch. A Pathol.
Anat. Histopathol. 1992, 420, 1–4. [Google Scholar] [CrossRef] [PubMed]
298. Bhanot, U.K.; Möller, P. Mechanisms of parenchymal injury and signaling
pathways in ectatic ducts of chronic pancreatitis: Implications for
pancreatic carcinogenesis. Lab. Investig. 2009, 89, 489–497. [Google
Scholar] [CrossRef] [PubMed]
299. Witt, H.; Apte, M.V.; Keim, V.; Wilson, J.S. Chronic pancreatitis:
Challenges and advances in pathogenesis, genetics, diagnosis, and therapy.
Gastroenterology 2007, 132, 1557–1573. [Google Scholar] [CrossRef]
[PubMed]
300. Yadav, D.; Whitcomb, D.C. The role of alcohol and smoking in pancreatitis.
Nat. Rev. Gastroenterol. Hepatol. 2010, 7, 131–145. [Google Scholar]
[CrossRef]
301. Whitcomb, D.C. Hereditary pancreatitis: New insights into acute and
chronic pancreatitis. Gut 1999, 45, 317–322. [Google Scholar] [CrossRef]
[PubMed]
302. Deng, X.; Wang, L.; Elm, M.S.; Gabazadeh, D.; Diorio, G.J.; Eagon, P.K.;
Whitcomb, D.C. Chronic alcohol consumption accelerates fibrosis in
response to cerulein-induced pancreatitis in rats. Am. J. Pathol. 2005,
166, 93–106. [Google Scholar] [CrossRef] [PubMed]
303. Leung, P.S.; Chan, Y.C. Role of oxidative stress in pancreatic
inflammation. Antioxid. Redox Signal. 2009, 11, 135–165. [Google Scholar]
[CrossRef] [PubMed]
304. Saito, I.; Hashimoto, S.; Saluja, A.; Steer, M.L.; Meldolesi, J.
Intracellular transport of pancreatic zymogens during caerulein
supramaximal stimulation. Am. J. Physiol. 1987, 253 Pt 1, G517–G526.
[Google Scholar] [CrossRef] [PubMed]
305. Norton, I.D.; Apte, M.V.; Lux, O.; Haber, P.S.; Pirola, R.C.; Wilson, J.S.
Chronic ethanol administration causes oxidative stress in the rat
pancreas. J. Lab. Clin. Med. 1998, 131, 442–446. [Google Scholar]
[CrossRef] [PubMed]
306. Yamaguchi, M.; Steward, M.C.; Smallbone, K.; Sohma, Y.; Yamamoto, A.; Ko,
S.B.; Kondo, T.; Ishiguro, H. Bicarbonate-rich fluid secretion predicted
by a computational model of guinea-pig pancreatic duct epithelium. J.
Physiol. 2017, 595, 1947–1972. [Google Scholar] [CrossRef] [PubMed]
307. Hall, P.A.; Lemoine, N.R. Rapid acinar to ductal transdifferentiation in
cultured human exocrine pancreas. J. Pathol. 1992, 166, 97–103. [Google
Scholar] [CrossRef]
308. Houbracken, I.; de Waele, E.; Lardon, J.; Ling, Z.; Heimberg, H.; Rooman,
I.; Bouwens, L. Lineage tracing evidence for transdifferentiation of
acinar to duct cells and plasticity of human pancreas. Gastroenterology
2011, 141, 731–741.e4. [Google Scholar] [CrossRef]
309. Weiss, F.U.; Skube, M.E.; Lerch, M.M. Chronic pancreatitis: An update on
genetic risk factors. Curr. Opin. Gastroenterol. 2018, 34, 322–329.
[Google Scholar] [CrossRef] [PubMed]
310. Moore, P.C.; Cortez, J.T.; Chamberlain, C.E.; Alba, D.; Berger, A.C.;
Quandt, Z.; Chan, A.; Cheng, M.H.; Bautista, J.L.; Peng, J.; et al.
Elastase 3B mutation links to familial pancreatitis with diabetes and
pancreatic adenocarcinoma. J. Clin. Investig. 2019, 129, 4676–4681.
[Google Scholar] [CrossRef] [PubMed]
311. Rebours, V.; Vullierme, M.P.; Hentic, O.; Maire, F.; Hammel, P.;
Ruszniewski, P.; Lévy, P. Smoking and the course of recurrent acute and
chronic alcoholic pancreatitis: A dose-dependent relationship. Pancreas
2012, 41, 1219–1224. [Google Scholar] [CrossRef] [PubMed]
312. Nikkola, J.; Räty, S.; Laukkarinen, J.; Seppänen, H.; Lappalainen-Lehto,
R.; Järvinen, S.; Nordback, I.; Sand, J. Abstinence after first acute
alcohol-associated pancreatitis protects against recurrent pancreatitis
and minimizes the risk of pancreatic dysfunction. Alcohol. Alcohol. 2013,
48, 483–486. [Google Scholar] [CrossRef] [PubMed]
313. Werner, J.; Laposata, M.; Fernández-del Castillo, C.; Saghir, M.; Iozzo,
R.V.; Lewandrowski, K.B.; Warshaw, A.L. Pancreatic injury in rats induced
by fatty acid ethyl ester, a nonoxidative metabolite of alcohol.
Gastroenterology 1997, 113, 286–294. [Google Scholar] [CrossRef]
314. Vonlaufen, A.; Wilson, J.S.; Pirola, R.C.; Apte, M.V. Role of alcohol
metabolism in chronic pancreatitis. Alcohol. Res. Health. 2007, 30, 48–54.
[Google Scholar] [PubMed]
315. Gu, H.; Werner, J.; Bergmann, F.; Whitcomb, D.C.; Büchler, M.W.;
Fortunato, F. Necro-inflammatory response of pancreatic acinar cells in
the pathogenesis of acute alcoholic pancreatitis. Cell Death Dis. 2013, 4,
e816. [Google Scholar] [CrossRef] [PubMed]
316. Apte, M.V.; Wilson, J.S. Stellate cell activation in alcoholic
pancreatitis. Pancreas 2003, 27, 316–320. [Google Scholar] [CrossRef]
[PubMed]
317. Hu, F.; Lou, N.; Jiao, J.; Guo, F.; Xiang, H.; Shang, D. Macrophages in
pancreatitis: Mechanisms and therapeutic potential. Biomed. Pharmacother.
2020, 131, 110693. [Google Scholar] [CrossRef]
318. Detlefsen, S.; Sipos, B.; Feyerabend, B.; Klöppel, G. Fibrogenesis in
alcoholic chronic pancreatitis: The role of tissue necrosis, macrophages,
myofibroblasts and cytokines. Mod. Pathol. 2006, 19, 1019–1026. [Google
Scholar] [CrossRef] [PubMed]
319. Shek, F.W.; Benyon, R.C.; Walker, F.M.; McCrudden, P.R.; Pender, S.L.;
Williams, E.J.; Johnson, P.A.; Johnson, C.D.; Bateman, A.C.; Fine, D.R.;
et al. Expression of transforming growth factor-beta 1 by pancreatic
stellate cells and its implications for matrix secretion and turnover in
chronic pancreatitis. Am. J. Pathol. 2002, 160, 1787–1798. [Google
Scholar] [CrossRef] [PubMed]
320. Bynigeri, R.R.; Jakkampudi, A.; Jangala, R.; Subramanyam, C.; Sasikala,
M.; Rao, G.V.; Reddy, D.N.; Talukdar, R. Pancreatic stellate cell:
Pandora’s box for pancreatic disease biology. World J. Gastroenterol.
2017, 23, 382–405. [Google Scholar] [CrossRef] [PubMed]
321. Zhang, H.; Liu, B.; Xu, X.F.; Jiang, T.T.; Zhang, X.Q.; Shi, Y.L.; Chen,
Y.; Liu, F.; Gu, J.; Zhu, L.J.; et al. Pathophysiology of chronic
pancreatitis induced by dibutyltin dichloride joint ethanol in mice. World
J. Gastroenterol. 2016, 22, 2960–2970. [Google Scholar] [CrossRef]
[PubMed]
322. Wu, J.; Zhang, L.; Shi, J.; He, R.; Yang, W.; Habtezion, A.; Niu, N.; Lu,
P.; Xue, J. Macrophage phenotypic switch orchestrates the inflammation and
repair/regeneration following acute pancreatitis injury. eBioMedicine
2020, 58, 102920. [Google Scholar] [CrossRef] [PubMed]
323. Shapouri-Moghaddam, A.; Mohammadian, S.; Vazini, H.; Taghadosi, M.;
Esmaeili, S.A.; Mardani, F.; Seifi, B.; Mohammadi, A.; Afshari, J.T.;
Sahebkar, A. Macrophage plasticity, polarization, and function in health
and disease. J. Cell Physiol. 2018, 233, 6425–6440. [Google Scholar]
[CrossRef] [PubMed]
324. Kishore, A.; Petrek, M. Roles of Macrophage Polarization and
Macrophage-Derived miRNAs in Pulmonary Fibrosis. Front. Immunol. 2021, 12,
678457. [Google Scholar] [CrossRef] [PubMed]
325. Lu, Y.; Lu, G.; Gao, L.; Zhu, Q.; Xue, J.; Zhang, J.; Ma, X.; Ma, N.;
Yang, Q.; Dong, J.; et al. The Proresolving Lipid Mediator Maresin1
Alleviates Experimental Pancreatitis via Switching Macrophage
Polarization. Mediat. Inflamm. 2021, 2021, 6680456. [Google Scholar]
[CrossRef] [PubMed]
326. Alho, H.; Sillanaukee, P.; Kalela, A.; Jaakkola, O.; Laine, S.; Nikkari,
S.T. Alcohol misuse increases serum antibodies to oxidized LDL and
C-reactive protein. Alcohol. Alcohol. 2004, 39, 312–315. [Google Scholar]
[CrossRef] [PubMed]
327. Gonzalez-Quintela, A.; Campos, J.; Loidi, L.; Quinteiro, C.; Perez, L.F.;
Gude, F. Serum TNF-alpha levels in relation to alcohol consumption and
common TNF gene polymorphisms. Alcohol 2008, 42, 513–518. [Google Scholar]
[CrossRef] [PubMed]
328. Apte, M.V.; Pirola, R.C.; Wilson, J.S. Mechanisms of alcoholic
pancreatitis. J. Gastroenterol. Hepatol. 2010, 25, 1816–1826. [Google
Scholar] [CrossRef]
329. Xue, J.; Sharma, V.; Hsieh, M.H.; Chawla, A.; Murali, R.; Pandol, S.J.;
Habtezion, A. Alternatively activated macrophages promote pancreatic
fibrosis in chronic pancreatitis. Nat. Commun. 2015, 6, 7158. [Google
Scholar] [CrossRef] [PubMed]
330. Żorniak, M.; Sirtl, S.; Mayerle, J.; Beyer, G. What Do We Currently Know
about the Pathophysiology of Alcoholic Pancreatitis: A Brief Review. Visc.
Med. 2020, 36, 182–190. [Google Scholar] [CrossRef]
331. Vogelmann, R.; Ruf, D.; Wagner, M.; Adler, G.; Menke, A. Effects of
fibrogenic mediators on the development of pancreatic fibrosis in a
TGF-beta1 transgenic mouse model. Am. J. Physiol. Gastrointest. Liver
Physiol. 2001, 280, G164–G172. [Google Scholar] [CrossRef]
332. Manohar, M.; Verma, A.K.; Venkateshaiah, S.U.; Sanders, N.L.; Mishra, A.
Pathogenic mechanisms of pancreatitis. World J. Gastrointest. Pharmacol.
Ther. 2017, 8, 10–25. [Google Scholar] [CrossRef] [PubMed]
333. Tang, D.; Wu, Q.; Zhang, J.; Zhang, H.; Yuan, Z.; Xu, J.; Chong, Y.;
Huang, Y.; Xiong, Q.; Wang, S.; et al. Galectin-1 expression in activated
pancreatic satellite cells promotes fibrosis in chronic
pancreatitis/pancreatic cancer via the TGF-β1/Smad pathway. Oncol. Rep.
2018, 39, 1347–1355. [Google Scholar] [CrossRef] [PubMed]
334. Lin, H.; Dong, B.; Qi, L.; Wei, Y.; Zhang, Y.; Cai, X.; Zhang, Q.; Li, J.;
Li, L. Inhibitory Smads suppress pancreatic stellate cell activation
through negative feedback in chronic pancreatitis. Ann. Transl. Med. 2021,
9, 384. [Google Scholar] [CrossRef] [PubMed]
335. An, W.; Zhu, J.W.; Jiang, F.; Jiang, H.; Zhao, J.L.; Liu, M.Y.; Li, G.X.;
Shi, X.G.; Sun, C.; Li, Z.S. Fibromodulin is upregulated by oxidative
stress through the MAPK/AP-1 pathway to promote pancreatic stellate cell
activation. Pancreatology 2020, 20, 278–287. [Google Scholar] [CrossRef]
[PubMed]
336. Xu, X.F.; Liu, F.; Xin, J.Q.; Fan, J.W.; Wu, N.; Zhu, L.J.; Duan, L.F.;
Li, Y.Y.; Zhang, H. Respective roles of the mitogen-activated protein
kinase (MAPK) family members in pancreatic stellate cell activation
induced by transforming growth factor-β1 (TGF-β1). Biochem. Biophys. Res.
Commun. 2018, 501, 365–373. [Google Scholar] [CrossRef] [PubMed]
337. Jin, G.; Hong, W.; Guo, Y.; Bai, Y.; Chen, B. Molecular Mechanism of
Pancreatic Stellate Cells Activation in Chronic Pancreatitis and
Pancreatic Cancer. J. Cancer. 2020, 11, 1505–1515. [Google Scholar]
[CrossRef] [PubMed]
338. Ramakrishnan, P.; Loh, W.M.; Gopinath, S.C.B.; Bonam, S.R.; Fareez, I.M.;
Mac Guad, R.; Sim, M.S.; Wu, Y.S. Selective phytochemicals targeting
pancreatic stellate cells as new anti-fibrotic agents for chronic
pancreatitis and pancreatic cancer. Acta Pharm. Sin B 2020, 10, 399–413.
[Google Scholar] [CrossRef] [PubMed]
339. Xue, R.; Jia, K.; Wang, J.; Yang, L.; Wang, Y.; Gao, L.; Hao, J. A Rising
Star in Pancreatic Diseases: Pancreatic Stellate Cells. Front. Physiol.
2018, 9, 754. [Google Scholar] [CrossRef] [PubMed]
340. Shimosegawa, T. A New Insight into Chronic Pancreatitis. Tohoku J. Exp.
Med. 2019, 248, 225–238. [Google Scholar] [CrossRef] [PubMed]
341. Luttenberger, T.; Schmid-Kotsas, A.; Menke, A.; Siech, M.; Beger, H.;
Adler, G.; Grünert, A.; Bachem, M.G. Platelet-derived growth factors
stimulate proliferation and extracellular matrix synthesis of pancreatic
stellate cells: Implications in pathogenesis of pancreas fibrosis. Lab.
Investig. 2000, 80, 47–55. [Google Scholar] [CrossRef] [PubMed]
342. Schneider, E.; Schmid-Kotsas, A.; Zhao, J.; Weidenbach, H.; Schmid, R.M.;
Menke, A.; Adler, G.; Waltenberger, J.; Grünert, A.; Bachem, M.G.
Identification of mediators stimulating proliferation and matrix synthesis
of rat pancreatic stellate cells. Am. J. Physiol. Cell Physiol. 2001, 281,
C532–C543. [Google Scholar] [CrossRef] [PubMed]
343. Phillips, P.A.; Wu, M.J.; Kumar, R.K.; Doherty, E.; McCarroll, J.A.; Park,
S.; Pirola, R.C.; Wilson, J.S.; Apte, M.V. Cell migration: A novel aspect
of pancreatic stellate cell biology. Gut 2003, 52, 677–682. [Google
Scholar] [CrossRef]
344. di Mola, F.F.; Friess, H.; Martignoni, M.E.; Di Sebastiano, P.;
Zimmermann, A.; Innocenti, P.; Graber, H.; Gold, L.I.; Korc, M.; Büchler,
M.W. Connective tissue growth factor is a regulator for fibrosis in human
chronic pancreatitis. Ann. Surg. 1999, 230, 63–71. [Google Scholar]
[CrossRef] [PubMed]
345. Gao, R.; Brigstock, D.R. Connective tissue growth factor (CCN2) in rat
pancreatic stellate cell function: Integrin alpha5beta1 as a novel CCN2
receptor. Gastroenterology 2005, 129, 1019–1030. [Google Scholar]
[CrossRef] [PubMed]
346. Karger, A.; Fitzner, B.; Brock, P.; Sparmann, G.; Emmrich, J.; Liebe, S.;
Jaster, R. Molecular insights into connective tissue growth factor action
in rat pancreatic stellate cells. Cell Signal. 2008, 20, 1865–1872.
[Google Scholar] [CrossRef] [PubMed]
347. Mews, P.; Phillips, P.; Fahmy, R.; Korsten, M.; Pirola, R.; Wilson, J.;
Apte, M. Pancreatic stellate cells respond to inflammatory cytokines:
Potential role in chronic pancreatitis. Gut 2002, 50, 535–541. [Google
Scholar] [CrossRef] [PubMed]
348. Marzoq, A.J.; Giese, N.; Hoheisel, J.D.; Alhamdani, M.S.S. Proteome
variations in pancreatic stellate cells upon stimulation with
proinflammatory factors. J. Biol. Chem. 2013, 288, 32517–32527. [Google
Scholar] [CrossRef] [PubMed]
349. Charo, C.; Holla, V.; Arumugam, T.; Hwang, R.; Yang, P.; Dubois, R.N.;
Menter, D.G.; Logsdon, C.D.; Ramachandran, V. Prostaglandin E2 regulates
pancreatic stellate cell activity via the EP4 receptor. Pancreas 2013, 42,
467–474. [Google Scholar] [CrossRef] [PubMed]
350. Huang, H.; Chen, J.; Peng, L.; Yao, Y.; Deng, D.; Zhang, Y.; Liu, Y.;
Wang, H.; Li, Z.; Bi, Y.; et al. Transgenic expression of cyclooxygenase-2
in pancreatic acinar cells induces chronic pancreatitis. Am. J. Physiol.
Gastrointest. Liver Physiol. 2019, 316, G179–G186. [Google Scholar]
[CrossRef] [PubMed]
351. Masamune, A.; Kikuta, K.; Watanabe, T.; Satoh, K.; Satoh, A.; Shimosegawa,
T. Pancreatic stellate cells express Toll-like receptors. J.
Gastroenterol. 2008, 43, 352–362. [Google Scholar] [CrossRef] [PubMed]
352. Xue, J.; Zhao, Q.; Sharma, V.; Nguyen, L.P.; Lee, Y.N.; Pham, K.L.;
Edderkaoui, M.; Pandol, S.J.; Park, W.; Habtezion, A. Aryl Hydrocarbon
Receptor Ligands in Cigarette Smoke Induce Production of Interleukin-22 to
Promote Pancreatic Fibrosis in Models of Chronic Pancreatitis.
Gastroenterology 2016, 151, 1206–1217. [Google Scholar] [CrossRef]
[PubMed]
353. Lee, A.T.; Xu, Z.; Pothula, S.P.; Patel, M.B.; Pirola, R.C.; Wilson, J.S.;
Apte, M.V. Alcohol and cigarette smoke components activate human
pancreatic stellate cells: Implications for the progression of chronic
pancreatitis. Alcohol. Clin. Exp. Res. 2015, 39, 2123–2133. [Google
Scholar] [CrossRef] [PubMed]
354. Gukovsky, I.; Pandol, S.J.; Mareninova, O.A.; Shalbueva, N.; Jia, W.;
Gukovskaya, A.S. Impaired autophagy and organellar dysfunction in
pancreatitis. J. Gastroenterol. Hepatol. 2012, 27 (Suppl. S2), 27–32.
[Google Scholar] [CrossRef] [PubMed]
355. Li, S.; Xie, K. Ductal metaplasia in pancreas. Biochim. Biophys. Acta Rev.
Cancer 2022, 1877, 188698. [Google Scholar] [CrossRef] [PubMed]
356. Parte, S.; Nimmakayala, R.K.; Batra, S.K.; Ponnusamy, M.P. Acinar to
ductal cell trans-differentiation: A prelude to dysplasia and pancreatic
ductal adenocarcinoma. Biochim. Biophys. Acta Rev. Cancer 2022, 1877,
188669. [Google Scholar] [CrossRef] [PubMed]
357. Masamune, A.; Kikuta, K.; Watanabe, T.; Satoh, K.; Hirota, M.;
Shimosegawa, T. Hypoxia stimulates pancreatic stellate cells to induce
fibrosis and angiogenesis in pancreatic cancer. Am. J. Physiol.
Gastrointest. Liver Physiol. 2008, 295, G709–G717. [Google Scholar]
[CrossRef] [PubMed]
358. Swain, S.M.; Romac, J.M.; Vigna, S.R.; Liddle, R.A. Piezo1-mediated
stellate cell activation causes pressure-induced pancreatic fibrosis in
mice. JCI Insight 2022, 7, e158288. [Google Scholar] [CrossRef] [PubMed]
359. Cannon, A.; Thompson, C.M.; Bhatia, R.; Armstrong, K.A.; Solheim, J.C.;
Kumar, S.; Batra, S.K. Molecular mechanisms of pancreatic myofibroblast
activation in chronic pancreatitis and pancreatic ductal adenocarcinoma.
J. Gastroenterol. 2021, 56, 689–703. [Google Scholar] [CrossRef] [PubMed]
360. Li, B.Q.; Liu, X.Y.; Mao, T.; Zheng, T.H.; Zhang, P.; Zhang, Q.; Zhang,
Y.; Li, X.Y. The research progress of anti-inflammatory and anti-fibrosis
treatment of chronic pancreatitis. Front. Oncol. 2022, 12, 1050274.
[Google Scholar] [CrossRef] [PubMed]
361. Kessler, A.; Weksler-Zangen, S.; Ilan, Y. Role of the Immune System and
the Circadian Rhythm in the Pathogenesis of Chronic Pancreatitis:
Establishing a Personalized Signature for Improving the Effect of
Immunotherapies for Chronic Pancreatitis. Pancreas 2020, 49, 1024–1032.
[Google Scholar] [CrossRef] [PubMed]
362. Hunger, R.E.; Mueller, C.; Z’graggen, K.; Friess, H.; Büchler, M.W.
Cytotoxic cells are activated in cellular infiltrates of alcoholic chronic
pancreatitis. Gastroenterology 1997, 112, 1656–1663. [Google Scholar]
[CrossRef] [PubMed]
363. Schmitz-Winnenthal, H.; Pietsch, D.H.; Schimmack, S.; Bonertz, A.; Udonta,
F.; Ge, Y.; Galindo, L.; Specht, S.; Volk, C.; Zgraggen, K.; et al.
Chronic pancreatitis is associated with disease-specific regulatory T-cell
responses. Gastroenterology 2010, 138, 1178–1188. [Google Scholar]
[CrossRef] [PubMed]
364. Grundsten, M.; Liu, G.Z.; Permert, J.; Hjelmstrom, P.; Tsai, J.A.
Increased central memory T cells in patients with chronic pancreatitis.
Pancreatology 2005, 5, 177–182. [Google Scholar] [CrossRef] [PubMed]
365. Kist, M.; Vucic, D. Cell death pathways: Intricate connections and disease
implications. EMBO J. 2021, 40, e106700. [Google Scholar] [CrossRef]
[PubMed]
366. Tang, D.; Kang, R.; Berghe, T.V.; Vandenabeele, P.; Kroemer, G. The
molecular machinery of regulated cell death. Cell Res. 2019, 29, 347–364.
[Google Scholar] [CrossRef] [PubMed]
367. Lee, P.J.; Papachristou, G.I. New insights into acute pancreatitis. Nat.
Rev. Gastroenterol. Hepatol. 2019, 16, 479–496. [Google Scholar]
[CrossRef]
368. Han, X.; Li, B.; Bao, J.; Wu, Z.; Chen, C.; Ni, J.; Shen, J.; Song, P.;
Peng, Q.; Wan, R.; et al. Endoplasmic reticulum stress promoted acinar
cell necroptosis in acute pancreatitis through cathepsinB-mediated AP-1
activation. Front. Immunol. 2022, 13, 968639. [Google Scholar] [CrossRef]
[PubMed]
369. Ma, N.; Yuan, C.; Shi, J.; Zhu, Q.; Liu, Y.; Ma, X.; Li, B.; Gong, W.;
Xue, J.; Lu, G.; et al. Interleukin-37 protects against acinar cell
pyroptosis in acute pancreatitis. JCI Insight. 2022, 7, e161244. [Google
Scholar] [CrossRef]
370. Li, H.Y.; Lin, Y.J.; Zhang, L.; Zhao, J.; Xiao, D.Y.; Huang, Z.Z.; Li,
P.W. Progress of pyroptosis in acute pancreatitis. Chin. Med. J. 2021,
134, 2160–2162. [Google Scholar] [CrossRef]
371. Chen, W.; Yuan, C.; Lu, Y.; Zhu, Q.; Ma, X.; Xiao, W.; Gong, W.; Huang,
W.; Xia, Q.; Lu, G.; et al. Tanshinone IIA Protects against Acute
Pancreatitis in Mice by Inhibiting Oxidative Stress via the Nrf2/ROS
Pathway. Oxid. Med. Cell Longev. 2020, 2020, 5390482. [Google Scholar]
[CrossRef] [PubMed]
372. Zhou, X.; Fu, Y.; Liu, W.; Mu, Y.; Zhang, H.; Chen, J.; Liu, P.
Ferroptosis in Chronic Liver Diseases: Opportunities and Challenges.
Front. Mol. Biosci. 2022, 9, 928321. [Google Scholar] [CrossRef] [PubMed]
373. Meng, Y.T.; Zhou, Y.; Han, P.Y.; Ren, H.B. Ferroptosis inhibition
attenuates inflammatory response in mice with acute hypertriglyceridemic
pancreatitis. World J. Gastroenterol. 2023, 29, 2294–2309. [Google
Scholar] [CrossRef] [PubMed]
374. Fortunato, F.; Bürgers, H.; Bergmann, F.; Rieger, P.; Büchler, M.W.;
Kroemer, G.; Werner, J. Impaired autolysosome formation correlates with
Lamp-2 depletion: Role of apoptosis, autophagy, and necrosis in
pancreatitis. Gastroenterology 2009, 137, 350–360.e5. [Google Scholar]
[CrossRef] [PubMed]
375. Li, N.; Wu, X.; Holzer, R.G.; Lee, J.H.; Todoric, J.; Park, E.J.; Ogata,
H.; Gukovskaya, A.S.; Gukovsky, I.; Pizzo, D.P.; et al. Loss of acinar
cell IKKα triggers spontaneous pancreatitis in mice. J. Clin. Investig.
2013, 123, 2231–2243. [Google Scholar] [CrossRef]
376. Mareninova, O.A.; Hermann, K.; French, S.W.; O’Konski, M.S.; Pandol, S.J.;
Webster, P.; Erickson, A.H.; Katunuma, N.; Gorelick, F.S.; Gukovsky, I.;
et al. Impaired autophagic flux mediates acinar cell vacuole formation and
trypsinogen activation in rodent models of acute pancreatitis. J. Clin.
Investig. 2009, 119, 3340–3355. [Google Scholar] [CrossRef] [PubMed]
377. Feng, D.; Park, O.; Radaeva, S.; Wang, H.; Yin, S.; Kong, X.; Zheng, M.;
Zakhari, S.; Kolls, J.K.; Gao, B. Interleukin-22 ameliorates
cerulein-induced pancreatitis in mice by inhibiting the autophagic
pathway. Int. J. Biol. Sci. 2012, 8, 249–257. [Google Scholar] [CrossRef]
[PubMed]
378. Wu, Y.; Tang, L.; Wang, B.; Sun, Q.; Zhao, P.; Li, W. The role of
autophagy in maintaining intestinal mucosal barrier. J. Cell Physiol.
2019, 234, 19406–19419. [Google Scholar] [CrossRef] [PubMed]
379. Larabi, A.; Barnich, N.; Nguyen, H.T.T. New insights into the interplay
between autophagy, gut microbiota and inflammatory responses in IBD.
Autophagy 2020, 16, 38–51. [Google Scholar] [CrossRef] [PubMed]
380. Wang, H.; Li, C.; Jiang, Y.; Li, H.; Zhang, D. Effects of Bacterial
Translocation and Autophagy on Acute Lung Injury Induced by Severe Acute
Pancreatitis. Gastroenterol. Res. Pract. 2020, 2020, 8953453. [Google
Scholar] [CrossRef] [PubMed]
381. Kong, L.; Deng, J.; Zhou, X.; Cai, B.; Zhang, B.; Chen, X.; Chen, Z.;
Wang, W. Sitagliptin activates the p62-Keap1-Nrf2 signalling pathway to
alleviate oxidative stress and excessive autophagy in severe acute
pancreatitis-related acute lung injury. Cell Death Dis. 2021, 12, 928.
[Google Scholar] [CrossRef] [PubMed]
382. Dolai, S.; Liang, T.; Orabi, A.I.; Holmyard, D.; Xie, L.; Greitzer-Antes,
D.; Kang, Y.; Xie, H.; Javed, T.A.; Lam, P.P.; et al. Pancreatitis-Induced
Depletion of Syntaxin 2 Promotes Autophagy and Increases Basolateral
Exocytosis. Gastroenterology 2018, 154, 1805–1821.e5. [Google Scholar]
[CrossRef] [PubMed]
383. Dolai, S.; Takahashi, T.; Qin, T.; Liang, T.; Xie, L.; Kang, F.; Miao,
Y.F.; Xie, H.; Kang, Y.; Manuel, J.; et al. Pancreas-specific SNAP23
depletion prevents pancreatitis by attenuating pathological basolateral
exocytosis and formation of trypsin-activating autolysosomes. Autophagy
2021, 17, 3068–3081. [Google Scholar] [CrossRef]
384. Huangfu, Y.; Yu, X.; Wan, C.; Zhu, Y.; Wei, Z.; Li, F.; Wang, Y.; Zhang,
K.; Li, S.; Dong, Y.; et al. Xanthohumol alleviates oxidative stress and
impaired autophagy in experimental severe acute pancreatitis through
inhibition of AKT/mTOR. Front. Pharmacol. 2023, 14, 1105726. [Google
Scholar] [CrossRef]
385. Inman, K.S.; Liu, Y.; Scotti Buzhardt, M.L.; Leitges, M.; Krishna, M.;
Crawford, H.C.; Fields, A.P.; Murray, N.R. Prkci Regulates Autophagy and
Pancreatic Tumorigenesis in Mice. Cancers 2022, 14, 796. [Google Scholar]
[CrossRef] [PubMed]
386. Massafra, V.; van Mil, S.W.C. Farnesoid X receptor: A “homeostat” for
hepatic nutrient metabolism. Biochim. Biophys. Acta Mol. Basis Dis. 2018,
1864, 45–59. [Google Scholar] [CrossRef]
387. Ding, L.; Yang, L.; Wang, Z.; Huang, W. Bile acid nuclear receptor FXR and
digestive system diseases. Acta Pharm. Sin. B 2015, 5, 135–144. [Google
Scholar] [CrossRef] [PubMed]
388. Hao, H.; Cao, L.; Jiang, C.; Che, Y.; Zhang, S.; Takahashi, S.; Wang, G.;
Gonzalez, F.J. Farnesoid X Receptor Regulation of the NLRP3 Inflammasome
Underlies Cholestasis-Associated Sepsis. Cell Metab. 2017, 25, 856–867.e5.
[Google Scholar] [CrossRef]
389. Zheng, Y.; Sun, W.; Wang, Z.; Liu, J.; Shan, C.; He, C.; Li, B.; Hu, X.;
Zhu, W.; Liu, L.; et al. Activation of Pancreatic Acinar FXR Protects
against Pancreatitis via Osgin1-Mediated Restoration of Efficient
Autophagy. Research 2022, 2022, 9784081. [Google Scholar] [CrossRef]
390. Vaccaro, M.I. Zymophagy: Selective autophagy of secretory granules. Int.
J. Cell Biol. 2012, 2012, 396705. [Google Scholar] [CrossRef]
391. Grasso, D.; Ropolo, A.; Lo Ré, A.; Boggio, V.; Molejón, M.I.; Iovanna,
J.L.; Gonzalez, C.D.; Urrutia, R.; Vaccaro, M.I. Zymophagy, a novel
selective autophagy pathway mediated by VMP1-USP9x-p62, prevents
pancreatic cell death. J. Biol. Chem. 2011, 286, 8308–8324. [Google
Scholar] [CrossRef]
392. Mareninova, O.A.; Dillon, D.L.; Wightman, C.J.M.; Yakubov, I.; Takahashi,
T.; Gaisano, H.Y.; Munson, K.; Ohmuraya, M.; Dawson, D.; Gukovsky, I.; et
al. Rab9 Mediates Pancreatic Autophagy Switch From Canonical to
Noncanonical, Aggravating Experimental Pancreatitis. Cell Mol.
Gastroenterol. Hepatol. 2022, 13, 599–622. [Google Scholar] [CrossRef]
[PubMed]
393. Hashimoto, D.; Ohmuraya, M.; Hirota, M.; Yamamoto, A.; Suyama, K.; Ida,
S.; Okumura, Y.; Takahashi, E.; Kido, H.; Araki, K.; et al. Involvement of
autophagy in trypsinogen activation within the pancreatic acinar cells. J.
Cell Biol. 2008, 181, 1065–1072. [Google Scholar] [CrossRef]
394. Ohmuraya, M.; Yamamura, K. Autophagy and acute pancreatitis: A novel
autophagy theory for trypsinogen activation. Autophagy 2008, 4, 1060–1062.
[Google Scholar] [CrossRef] [PubMed]
395. Gukovskaya, A.S.; Gukovsky, I. Autophagy and pancreatitis. Am. J. Physiol.
Gastrointest. Liver Physiol. 2012, 303, G993–G1003. [Google Scholar]
[CrossRef] [PubMed]
396. Voronina, S.; Chvanov, M.; De Faveri, F.; Mayer, U.; Wileman, T.; Criddle,
D.; Tepikin, A. Autophagy, Acute Pancreatitis and the Metamorphoses of a
Trypsinogen-Activating Organelle. Cells. 2022, 11, 2514. [Google Scholar]
[CrossRef] [PubMed]
397. Gukovskaya, A.S.; Gorelick, F.S.; Groblewski, G.E.; Mareninova, O.A.;
Lugea, A.; Antonucci, L.; Waldron, R.T.; Habtezion, A.; Karin, M.; Pandol,
S.J.; et al. Recent Insights Into the Pathogenic Mechanism of
Pancreatitis: Role of Acinar Cell Organelle Disorders. Pancreas 2019, 48,
459–470. [Google Scholar] [CrossRef] [PubMed]
398. Courreges, A.P.; Najenson, A.C.; Vatta, M.S.; Bianciotti, L.G. Atrial
natriuretic peptide attenuates endoplasmic reticulum stress in
experimental acute pancreatitis. Biochim. Biophys. Acta Mol. Basis Dis.
2019, 1865, 485–493. [Google Scholar] [CrossRef] [PubMed]
399. Logsdon, C.D.; Ji, B. The role of protein synthesis and digestive enzymes
in acinar cell injury. Nat. Rev. Gastroenterol. Hepatol. 2013, 10,
362–370. [Google Scholar] [CrossRef] [PubMed]
400. Park, S.; Zuber, C.; Roth, J. Selective autophagy of cytosolic protein
aggregates involves ribosome-free rough endoplasmic reticulum. Histochem.
Cell Biol. 2020, 153, 89–99. [Google Scholar] [CrossRef] [PubMed]
401. Calvo-Garrido, J.; Escalante, R. Autophagy dysfunction and
ubiquitin-positive protein aggregates in Dictyostelium cells lacking Vmp1.
Autophagy 2010, 6, 100–109. [Google Scholar] [CrossRef] [PubMed]
402. Xu, B.; Bai, B.; Sha, S.; Yu, P.; An, Y.; Wang, S.; Kong, X.; Liu, C.;
Wei, N.; Feng, Q.; et al. Interleukin-1β induces autophagy by affecting
calcium homeostasis and trypsinogen activation in pancreatic acinar cells.
Int. J. Clin. Exp. Pathol. 2014, 7, 3620–3631. [Google Scholar] [PubMed]
403. Dolai, S.; Liang, T.; Orabi, A.I.; Xie, L.; Holmyard, D.; Javed, T.A.;
Fernandez, N.A.; Xie, H.; Cattral, M.S.; Thurmond, D.C.; et al. Depletion
of the membrane-fusion regulator Munc18c attenuates caerulein
hyperstimulation-induced pancreatitis. J. Biol. Chem. 2018, 293,
2510–2522. [Google Scholar] [CrossRef] [PubMed]
404. Walter, P.; Ron, D. The unfolded protein response: From stress pathway to
homeostatic regulation. Science 2011, 334, 1081–1086. [Google Scholar]
[CrossRef] [PubMed]
405. Lugea, A.; Waldron, R.T.; French, S.W.; Pandol, S.J. Drinking and driving
pancreatitis: Links between endoplasmic reticulum stress and autophagy.
Autophagy 2011, 7, 783–785. [Google Scholar] [CrossRef] [PubMed]
406. Hall, J.C.; Crawford, H.C. The conspiracy of autophagy, stress and
inflammation in acute pancreatitis. Curr. Opin. Gastroenterol. 2014, 30,
495–499. [Google Scholar] [CrossRef]
407. Mareninova, O.A.; Jia, W.; Gretler, S.R.; Holthaus, C.L.; Thomas, D.D.H.;
Pimienta, M.; Dillon, D.L.; Gukovskaya, A.S.; Gukovsky, I.; Groblewski,
G.E. Transgenic expression of GFP-LC3 perturbs autophagy in exocrine
pancreas and acute pancreatitis responses in mice. Autophagy 2020, 16,
2084–2097. [Google Scholar] [CrossRef] [PubMed]
408. Chen, Y.; Zhang, J.; Zhao, Q.; Chen, Q.; Sun, Y.; Jin, Y.; Wu, J.
Melatonin Induces Anti-Inflammatory Effects to Play a Protective Role via
Endoplasmic Reticulum Stress in Acute Pancreatitis. Cell Physiol. Biochem.
2016, 40, 1094–1104. [Google Scholar] [CrossRef] [PubMed]
409. Fazio, E.N.; Dimattia, G.E.; Chadi, S.A.; Kernohan, K.D.; Pin, C.L.
Stanniocalcin 2 alters PERK signalling and reduces cellular injury during
cerulein induced pancreatitis in mice. BMC Cell Biol. 2011, 12, 17.
[Google Scholar] [CrossRef] [PubMed]
410. Biczó, G.; Hegyi, P.; Dósa, S.; Shalbuyeva, N.; Berczi, S.; Sinervirta,
R.; Hracskó, Z.; Siska, A.; Kukor, Z.; Jármay, K.; et al. The crucial role
of early mitochondrial injury in L-lysine-induced acute pancreatitis.
Antioxid. Redox Signal. 2011, 15, 2669–2681. [Google Scholar] [CrossRef]
[PubMed]
411. Choi, J.; Oh, T.G.; Jung, H.W.; Park, K.Y.; Shin, H.; Jo, T.; Kang, D.S.;
Chanda, D.; Hong, S.; Kim, J.; et al. Estrogen-Related Receptor γ
Maintains Pancreatic Acinar Cell Function and Identity by Regulating
Cellular Metabolism. Gastroenterology 2022, 163, 239–256. [Google Scholar]
[CrossRef] [PubMed]
412. Shirihai, O.S.; Song, M.; Dorn, G.W., 2nd. How mitochondrial dynamism
orchestrates mitophagy. Circ. Res. 2015, 116, 1835–1849. [Google Scholar]
[CrossRef] [PubMed]
413. Vanasco, V.; Ropolo, A.; Grasso, D.; Ojeda, D.S.; García, M.N.; Vico,
T.A.; Orquera, T.; Quarleri, J.; Alvarez, S.; Vaccaro, M.I. Mitochondrial
Dynamics and VMP1-Related Selective Mitophagy in Experimental Acute
Pancreatitis. Front. Cell Dev. Biol. 2021, 9, 640094. [Google Scholar]
[CrossRef] [PubMed]
414. Wen, E.; Xin, G.; Su, W.; Li, S.; Zhang, Y.; Dong, Y.; Yang, X.; Wan, C.;
Chen, Z.; Yu, X.; et al. Activation of TLR4 induces severe acute
pancreatitis-associated spleen injury via ROS-disrupted mitophagy pathway.
Mol. Immunol. 2022, 142, 63–75. [Google Scholar] [CrossRef] [PubMed]
415. Zhi, X.; Feng, W.; Rong, Y.; Liu, R. Anatomy of autophagy: From the
beginning to the end. Cell Mol. Life Sci. 2018, 75, 815–831. [Google
Scholar] [CrossRef] [PubMed]
416. Savini, M.; Zhao, Q.; Wang, M.C. Lysosomes: Signaling Hubs for Metabolic
Sensing and Longevity. Trends Cell Biol. 2019, 29, 876–887. [Google
Scholar] [CrossRef]
417. Nowosad, A.; Besson, A. Lysosomes at the Crossroads of Cell Metabolism,
Cell Cycle, and Stemness. Int. J. Mol. Sci. 2022, 23, 2290. [Google
Scholar] [CrossRef] [PubMed]
418. Reiser, J.; Adair, B.; Reinheckel, T. Specialized roles for cysteine
cathepsins in health and disease. J. Clin. Investig. 2010, 120, 3421–3431.
[Google Scholar] [CrossRef] [PubMed]
419. Eskelinen, E.L.; Tanaka, Y.; Saftig, P. At the acidic edge: Emerging
functions for lysosomal membrane proteins. Trends Cell Biol. 2003, 13,
137–145. [Google Scholar] [CrossRef] [PubMed]
420. Saftig, P.; Klumperman, J. Lysosome biogenesis and lysosomal membrane
proteins: Trafficking meets function. Nat. Rev. Mol. Cell Biol. 2009, 10,
623–635. [Google Scholar] [CrossRef]
421. Saluja, A.; Hashimoto, S.; Saluja, M.; Powers, R.E.; Meldolesi, J.; Steer,
M.L. Subcellular redistribution of lysosomal enzymes during
caerulein-induced pancreatitis. Am. J. Physiol. 1987, 253 Pt 1, G508–G516.
[Google Scholar] [CrossRef] [PubMed]
422. Tan, A.; Prasad, R.; Lee, C.; Jho, E.H. Past, present, and future
perspectives of transcription factor EB (TFEB): Mechanisms of regulation
and association with disease. Cell Death Differ. 2022, 29, 1433–1449.
[Google Scholar] [CrossRef] [PubMed]
423. Napolitano, G.; Ballabio, A. TFEB at a glance. J. Cell Sci. 2016, 129,
2475–2481. [Google Scholar] [CrossRef] [PubMed]
424. Wang, S.; Ni, H.M.; Chao, X.; Wang, H.; Bridges, B.; Kumer, S.; Schmitt,
T.; Mareninova, O.; Gukovskaya, A.; De Lisle, R.C.; et al. Impaired
TFEB-mediated lysosomal biogenesis promotes the development of
pancreatitis in mice and is associated with human pancreatitis. Autophagy
2019, 15, 1954–1969. [Google Scholar] [CrossRef] [PubMed]
425. Wang, S.; Ni, H.M.; Chao, X.; Ma, X.; Kolodecik, T.; De Lisle, R.;
Ballabio, A.; Pacher, P.; Ding, W.X. Critical Role of TFEB-Mediated
Lysosomal Biogenesis in Alcohol-Induced Pancreatitis in Mice and Humans.
Cell Mol. Gastroenterol. Hepatol. 2020, 10, 59–81. [Google Scholar]
[CrossRef] [PubMed]
426. Mizushima, N. The ubiquitin E2 enzyme UBE2QL1 mediates lysophagy. EMBO
Rep. 2019, 20, e49104. [Google Scholar] [CrossRef] [PubMed]
427. Maejima, I.; Takahashi, A.; Omori, H.; Kimura, T.; Takabatake, Y.; Saitoh,
T.; Yamamoto, A.; Hamasaki, M.; Noda, T.; Isaka, Y.; et al. Autophagy
sequesters damaged lysosomes to control lysosomal biogenesis and kidney
injury. EMBO J. 2013, 32, 2336–2347. [Google Scholar] [CrossRef] [PubMed]
428. Iwama, H.; Mehanna, S.; Imasaka, M.; Hashidume, S.; Nishiura, H.;
Yamamura, K.I.; Suzuki, C.; Uchiyama, Y.; Hatano, E.; Ohmuraya, M.
Cathepsin B and D deficiency in the mouse pancreas induces impaired
autophagy and chronic pancreatitis. Sci. Rep. 2021, 11, 6596. [Google
Scholar] [CrossRef] [PubMed]
429. Yuan, X.; Wu, J.; Guo, X.; Li, W.; Luo, C.; Li, S.; Wang, B.; Tang, L.;
Sun, H. Autophagy in Acute Pancreatitis: Organelle Interaction and
microRNA Regulation. Oxid. Med. Cell Longev. 2021, 2021, 8811935. [Google
Scholar] [CrossRef] [PubMed]
430. Sun, H.; Tian, J.; Li, J. MiR-92b-3p ameliorates inflammation and
autophagy by targeting TRAF3 and suppressing MKK3-p38 pathway in
caerulein-induced AR42J cells. Int. Immunopharmacol. 2020, 88, 106691.
[Google Scholar] [CrossRef]
431. Xiao, J.; Feng, X.; Huang, X.Y.; Huang, Z.; Huang, Y.; Li, C.; Li, G.;
Nong, S.; Wu, R.; Huang, Y.; et al. Spautin-1 Ameliorates Acute
Pancreatitis via Inhibiting Impaired Autophagy and Alleviating Calcium
Overload. Mol. Med. 2016, 22, 643–652. [Google Scholar] [CrossRef]
[PubMed]
432. Xiao, J.; Lin, H.; Liu, B.; Jin, J. CaMKII/proteasome/cytosolic
calcium/cathepsin B axis was present in tryspin activation induced by
nicardipine. Biosci. Rep. 2019, 39, BSR20190516. [Google Scholar]
[CrossRef] [PubMed]
433. Zalcman, G.; Federman, N.; Romano, A. CaMKII Isoforms in Learning and
Memory: Localization and Function. Front. Mol. Neurosci. 2018, 11, 445.
[Google Scholar] [CrossRef] [PubMed]
434. Ji, L.; Wang, Z.H.; Zhang, Y.H.; Zhou, Y.; Tang, D.S.; Yan, C.S.; Ma,
J.M.; Fang, K.; Gao, L.; Ren, N.S.; et al. ATG7-enhanced impaired
autophagy exacerbates acute pancreatitis by promoting regulated necrosis
via the miR-30b-5p/CAMKII pathway. Cell Death Dis. 2022, 13, 211. [Google
Scholar] [CrossRef] [PubMed]
435. Yu, J.H.; Kim, H. Role of janus kinase/signal transducers and activators
of transcription in the pathogenesis of pancreatitis and pancreatic
cancer. Gut Liver 2012, 6, 417–422. [Google Scholar] [CrossRef] [PubMed]
436. Yang, S.; Imamura, Y.; Jenkins, R.W.; Cañadas, I.; Kitajima, S.; Aref, A.;
Brannon, A.; Oki, E.; Castoreno, A.; Zhu, Z.; et al. Autophagy Inhibition
Dysregulates TBK1 Signaling and Promotes Pancreatic Inflammation. Cancer
Immunol. Res. 2016, 4, 520–530. [Google Scholar] [CrossRef] [PubMed]
437. Kubisch, C.H.; Logsdon, C.D. Endoplasmic reticulum stress and the
pancreatic acinar cell. Expert Rev. Gastroenterol. Hepatol. 2008, 2,
249–260. [Google Scholar] [CrossRef] [PubMed]
438. Sah, R.P.; Garg, S.K.; Dixit, A.K.; Dudeja, V.; Dawra, R.K.; Saluja, A.K.
Endoplasmic reticulum stress is chronically activated in chronic
pancreatitis. J. Biol. Chem. 2014, 289, 27551–27561. [Google Scholar]
[CrossRef] [PubMed]
439. Zhang, K.; Kaufman, R.J. From endoplasmic-reticulum stress to the
inflammatory response. Nature 2008, 454, 455–462. [Google Scholar]
[CrossRef] [PubMed]
440. Netea-Maier, R.T.; Plantinga, T.S.; van de Veerdonk, F.L.; Smit, J.W.;
Netea, M.G. Modulation of inflammation by autophagy: Consequences for
human disease. Autophagy 2016, 12, 245–260. [Google Scholar] [CrossRef]
441. Martins, J.D.; Liberal, J.; Silva, A.; Ferreira, I.; Neves, B.M.; Cruz,
M.T. Autophagy and inflammasome interplay. DNA Cell Biol. 2015, 34,
274–281. [Google Scholar] [CrossRef] [PubMed]
442. Zhang, T.; Gan, Y.; Zhu, S. Association between autophagy and acute
pancreatitis. Front. Genet. 2023, 14, 998035. [Google Scholar] [CrossRef]
[PubMed]
443. Hey-Hadavi, J.; Velisetty, P.; Mhatre, S. Trends and recent developments
in pharmacotherapy of acute pancreatitis. Postgrad. Med. 2023, 135,
334–344. [Google Scholar] [CrossRef] [PubMed]
444. Zaman, S.; Gorelick, F. Acute pancreatitis: Pathogenesis and emerging
therapies. J. Pancreatol. 2024, 7, 10–20. [Google Scholar] [CrossRef]
445. Yang, H.; Ma, S.; Guo, Y.; Cui, D.; Yao, J. Bidirectional effects of
pyrrolidine dithiocarbamate on severe acute pancreatitis in a rat model.
Dose. Response 2019, 17, 1559325819825905. [Google Scholar] [CrossRef]
[PubMed]
446. Wan, J.; Chen, J.; Wu, D.; Yang, X.; Ouyang, Y.; Zhu, Y.; Xia, L.; Lu, N.
Regulation of autophagy affects the prognosis of mice with severe acute
pancreatitis. Dig. Dis. Sci. 2018, 63, 2639–2650. [Google Scholar]
[CrossRef] [PubMed]
447. Yang, S.; Bing, M.; Chen, F.; Sun, Y.; Chen, H.; Chen, W. Autophagy
regulation by the nuclear factor kB signal axis in acute pancreatis.
Pancreas 2012, 41, 367–373. [Google Scholar] [CrossRef] [PubMed]
448. Fu, X.; Xiu, Z.; Xu, H. Interleukin-22 and acute pancreatitis: A review.
Medicine 2023, 102, e35695. [Google Scholar] [CrossRef] [PubMed]
449. Fu, X.; Xiu, Z.; Xu, Q.; Yue, R.; Xu, H. Interleukin-22 Alleviates
Caerulein-Induced Acute Pancreatitis by Activating AKT/mTOR Pathway. Dig.
Dis. Sci. 2024; Online ahead of print. [Google Scholar] [CrossRef]
450. Dong, K.; Chen, X.; Xie, L.; Yu, L.; Shen, M.; Wang, Y.; Wu, S.; Wang, J.;
Lu, J.; Wei, G.; et al. Spautin-A41 Attenuates Cerulein-Induced Acute
Pancreatitis through Inhibition of Dysregulated Autophagy. Biol. Pharm.
Bull. 2019, 42, 1789–1798. [Google Scholar] [CrossRef] [PubMed]
Figure 1. A simplified diagram of autophagy regulation. Black arrows:
activation. Red arrows: inhibition. Intermittent arrows: cleavage. Certain
pathways have been omitted for clarity. See text for more details. Bcl-2: B-cell
lymphoma-2; FADD: Fas-associating protein with death domain; TRADD: Tumor
necrosis factor receptor type 1-associated DEATH domain protein; RIPK1: Receptor
Interacting Serine/Threonine Kinase 1.
Figure 2. Pathogenesis of acute pancreatitis. Black arrows: activation. Red
arrows: inhibition. ER: endoplasmic reticulum; MPTP: mitochondrial permeability
transition pores; ATP: adenosine triphosphate; CHOP: CEBP homologous protein;
DAMPS: damage associated molecular patterns; ETOH: Alcohol; SERCA: smooth ER
Ca++ channels; PMCA: plasma membrane Ca++ channels; UPR: unfolded protein
response.
Figure 3. Inflammation in acute and chronic pancreatitis. Black arrows:
activation. For more details, see text. LPS: lipopolysaccharide; HSP70: heat
shock protein 70; HMGB1: high mobility group box 1; TLR4,9: toll like receptor
4,9; ROS: reactive oxygen species; ATP: adenosine triphosphate; NETS: neutrophil
extracellular traps; NLRP3: NLR pyrin domain containing protein 3; ASC: caspase
recruitment domain; NOD1: nucleotide-binding oligomerization domain 1; MCP1:
monocyte chemoattractant protein 1; mtDNA: mitochondrial DNA; PSC: Pancreatic
stellate cells; MIP2: Macrophage inflammatory protein-2.
Table 1. Main studies on the role of autophagy in pancreatitis.
Original StudiesOutcomesReferencesDeletions of Atg5 or Atg7 or of the inhibitor
of nuclear factor IκB kinase α (IKKα) ER stress and accumulation of
dysfunctional mitochondria unable to generate ATP[178,271]Atg5 deletion Reduced
severity of the disease paralleled with the reduced trypsinogen
activation[393,394]LAMP2 deficiency Increased severity of cerulein
pancreatitis[270,374]Administration of the enhancer of autophagy trehalose
Reduced trypsinogen activation and necrosis[122]Reduced autophagy in severe
APImpaired tight junctions. Reduction of the function of goblet and Paneth
cells. Increased bacterial translocation and extra-pancreatic
manifestations[370,378,379]Zymogen exocytosis and autophagy. SNARE proteinsBlock
of the fusion of zymogen granules with the plasma membrane and
exocytosis[382,383]Pancreatic Protein kinase C iota (PKCi) deletionDisruption of
autophagy. Increased sensitivity to cerulein-induced pancreatitis
[385]Stimulation of autophagic flux by the FXR-OSGIN1 axisProtection from
pancreatitis[389]Increased zymophagyProtection from pancreatitis[390,391] Rab9
decrease Boost of canonical autophagy and mitigation of disease severity
[392]Xanthohumol administrationInhibition of mTOR. Restoration of autophagy.
Reduction of pancreatitis severity[384]ER stressActivation of trypsinogen and
impaired autophagy[402,403,404,407]ROS overproductionMitophagy disruption.
Activation of AKT/mTOR pathway. Severe AP[414][407] Dysfunction of the lysosomes
Autophagy block. Pancreatitis[376,395,419]Deletion/degradation of TFEBAutophagy
impairment. Increased severity of pancreatitis.[424,425]
The associations between autophagy and pancreatitis were recently reviewed
[442].
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Tsomidis, I.; Voumvouraki, A.; Kouroumalis, E. The Pathogenesis of Pancreatitis
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