Chronic stress sensitizes rats to pancreatitis induced by cerulein:Role of TNF-α

查看全文 作　　者：Marcelo G [1,2]Binker;Andres A Binker-[1]Cosen;Daniel [1]Richards;Herbert Y [2]Gaisano;Rodica H de [1]Cosen;Laura I Cosen-[1,2]Binker 机构地区：[1]CBRHC Research Health Center;[2]Department of Medicine and Physiology,University of Toronto 出　　处：《World Journal of Gastroenterology》索引2010年第16卷第44期,共17页 基　　金：Supported by KB Certification International 摘　　要：AIM:To investigate chronic stress as a susceptibility factor for developing pancreatitis,as well as tumor necrosis factor-α (TNF-α) as a putative sensitizer.METHODS:Rat pancreatic acini were used to analyze the influence of TNF-α on submaximal (50 pmol/L) cholecystokinin (CCK) stimulation.Chronic restraint (4 h every day for 21 d) was used to evaluate the effects of submaximal (0.2 μg/kg per hour) cerulein stimulation on chronically stressed rats.RESULTS:In vitro exposure of pancreatic acini toTNF-α disorganized the actin cytoskeleton.This was further increased by TNF-α/CCK treatment,which additionally reduced amylase secretion,and increased trypsin and nuclear factor-κB activities in a protein-kinase-C δ and ε-dependent manner.TNF-α/CCK also enhanced caspases' activity and lactate dehydrogenase release,induced ATP loss,and augmented the ADP/ATP ratio.In vivo,rats under chronic restraint exhibited elevated serum and pancreatic TNF-α levels.Serum,pancreatic,and lung inflammatory parameters,as well as caspases' activity in pancreatic and lung tissue,were substantially enhanced in stressed/cerulein-treated rats,which also experienced tissues' ATP loss and greater ADP/ATP ratios.Histological examination revealed that stressed/cerulein-treated animals developed abundant pancreatic and lung edema,hemorrhage and leukocyte infiltrate,and pancreatic necrosis.Pancreatitis severity was greatly decreased by treating animals with an anti-TNF-αantibody,which diminished all inflammatory parameters,histopathological scores,and apoptotic/necrotic markers in stressed/cerulein-treated rats.CONCLUSION:In rats,chronic stress increases susceptibility for developing pancreatitis,which involves TNF-α sensitization of pancreatic acinar cells to undergo injury by physiological cerulein stimulation. 关 键 词：PANCREATITIS STRESS Tumor necrosis factor-α