Original Article
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World J Gastroenterol. Nov 28, 2010; 16(44): 5565-5581
Published online Nov 28, 2010. doi: 10.3748/wjg.v16.i44.5565
Chronic stress sensitizes rats to pancreatitis induced by cerulein: Role of TNF-α
Marcelo G Binker, Andres A Binker-Cosen, Daniel Richards, Herbert Y Gaisano, Rodica H de Cosen, Laura I Cosen-Binker
Marcelo G Binker, Andres A Binker-Cosen, Daniel Richards, Rodica H de Cosen, Laura I Cosen-Binker, CBRHC Research Health Center, Buenos Aires, 1426, Argentina
Marcelo G Binker, Herbert Y Gaisano, Laura I Cosen-Binker, Department of Medicine and Physiology, University of Toronto, Toronto, Ontario M58 1A8, Canada
Author contributions: Binker MG and Cosen-Binker LI conceived and designed the study; Binker MG, Binker-Cosen AA, Richards D and de Cosen RH acquired the data; Binker MG, Binker-Cosen AA, Gaisano HY, de Cosen RH and Cosen-Binker LI analyzed and interpreted the data; Binker MG drafted the manuscript; Binker MG and Richards D performed the statistical analysis; Richards D lent technical support; Gaisano HY, de Cosen RH and Cosen-Binker LI critically revised the manuscript for important intellectual content; Cosen-Binker LI obtained the funding, provided technical and material support, and supervised the study.
Supported by KB Certification International
Correspondence to: Dr. Laura I Cosen-Binker, CBRHC Research Health Center, Arribenos 1697, P.1, Buenos Aires, 1426, Argentina. laura.cosen.binker@utoronto.ca
Telephone: +54-11-47847365 Fax: +54-11-47847365
Received: July 17, 2010
Revised: August 5, 2010
Accepted: August 12, 2010
Published online: November 28, 2010
Abstract

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 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.

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.

Keywords: Pancreatitis; Stress; Tumor necrosis factor-α