title: Chronic stress sensitizes rats to pancreatitis induced by cerulein: role of TNF-α.
abstract: OBJECTIVE
  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 to TNF-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-α-antibody, which diminished all inflammatory parameters, histopathological scores, and apoptotic/necrotic markers in stressed/cerulein-treated rats.
  
  
  CONCLUSIONS
  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.
authors.affiliation: CBRHC Research Health Center, Arribenos 1697, P.1, Buenos Aires 1426, Argentina.
authors.forename: Marcelo-G
authors.initials: MG
authors.lastname: Binker
authors.forename: Andres-A
authors.initials: AA
authors.lastname: Binker-Cosen
authors.forename: Daniel
authors.initials: D
authors.lastname: Richards
authors.forename: Herbert-Y
authors.initials: HY
authors.lastname: Gaisano
authors.forename: Rodica-H
authors.initials: RH
authors.lastname: de Cosen
authors.forename: Laura-I
authors.initials: LI
authors.lastname: Cosen-Binker
mesh_terms: D000199:Actins / Q000378:metabolism; D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000681:Amylases / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D020013:Calcium Signaling; D020169:Caspases / Q000378:metabolism; D002108:Ceruletide; D002766:Cholecystokinin / Q000378:metabolism; D002908:Chronic Disease; D003599:Cytoskeleton / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D055370:Lung Injury / Q000209:etiology / Q000276:immunology / Q000523:psychology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D046790:Pancreas, Exocrine / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control / Q000523:psychology*; D051745:Protein Kinase C-delta / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D017208:Rats, Wistar; D012149:Restraint, Physical; D012720:Severity of Illness Index; D013315:Stress, Psychological / Q000150:complications*; D046509:Tissue Culture Techniques; D014357:Trypsin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*
chemical_list: D000199:Actins; D000906:Antibodies; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D000244:Adenosine Diphosphate; D002108:Ceruletide; D000255:Adenosine Triphosphate; D002766:Cholecystokinin; C497260:Prkcd protein, rat; C497257:Prkce protein, rat; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon; D000681:Amylases; D014357:Trypsin; D020169:Caspases