Trypsin in pancreatitis:The culprit,a mediator,or epiphenomenon?  

作　　者：Anna S Gukovskaya Markus M Lerch Julia Mayerle Matthias Sendler Baoan Ji Ashok K Saluja Fred S Gorelick Ilya Gukovsky 

机构地区：[1]Department of Medicine,David Geffen School of Medicine,University of California at Los Angeles,Los Angeles,CA 90073,United States Department of Medicine,VA Greater Los Angeles [2]Healthcare System,Los Angeles,CA 90073,United States [3]Department of Medicine,Ludwig Maximilian University Hospital,Munich 81377,Germany [4]Department of Medicine II,Ludwig Maximilian University of Munich,Munich 81377,Germany [5]Department of Medicine A,University of Greifswald,Greifswald 17475,Germany [6]Department of Cancer Biology,Mayo Clinic,Jacksonville,FL 32224,United States [7]Department of Surgery,University of Miami Miller School of Medicine,Miami,FL 33136,United States [8]Departments of Cell Biology and Internal Medicine,Yale University School of Medicine and VA West Haven,New Haven,CT 06519,United States

出　　处：《World Journal of Gastroenterology》2024年第41期4417-4438,共22页世界胃肠病学杂志（英文）

摘　　要：Pancreatitis is a common,life-threatening inflammatory disease of the exocrine pancreas.Its pathogenesis remains obscure,and no specific or effective treatment is available.Gallstones and alcohol excess are major etiologies of pancreatitis;in a small portion of patients the disease is hereditary.Pancreatitis is believed to be initiated by injured acinar cells(the main exocrine pancreas cell type),leading to parenchymal necrosis and local and systemic inflammation.The primary function of these cells is to produce,store,and secrete a variety of enzymes that break down all categories of nutrients.Most digestive enzymes,including all proteases,are secreted by acinar cells as inactive proforms(zymogens)and in physiological conditions are only activated when reaching the intestine.The generation of trypsin from inactive trypsinogen in the intestine plays a critical role in physiological activation of other zymogens.It was proposed that pancreatitis results from proteolytic autodigestion of the gland,mediated by premature/inappropriate trypsinogen activation within acinar cells.The intra-acinar trypsinogen activation is observed in experimental models of acute and chronic pancreatitis,and in human disease.On the basis of these observations,it has been considered the central pathogenic mechanism of pancreatitis-a concept with a century-old history.This review summarizes the data on trypsinogen activation in experimental and genetic rodent models of pancreatitis,particularly the more recent genetically engineered mouse models that mimic mutations associated with hereditary pancreatitis;analyzes the mechanisms mediating trypsinogen activation and protecting the pancreas against its’damaging effects;discusses the gaps in our knowledge,potential therapeutic approaches,and directions for future research.We conclude that trypsin is not the culprit in the disease pathogenesis but,at most,a mediator of some pancreatitis responses.Therefore,the search for effective therapies should focus on approaches to prevent or normalize ot

关 键 词：Pancreatic acinar cell Hereditary pancreatitis Autophagy Endolysosomal system CHOLECYSTOKININ CERULEIN CATHEPSIN 

分 类 号：R576[医药卫生—消化系统]