title: Protective role of endogenous nitric oxide (NO) in lipopolysaccharide--induced pancreatic damage (a new experimental model of acute pancreatitis).
abstract: Lipopolysaccharide (LPS) derived from the bacterial cell wall activates the inflammatory response in the tissue but the role of LPS in the pathogenesis of pancreatic damage and in the activation of NO system in the pancreas has not been fully explained. The aim of this study was to investigate the effect of repeated administration of LPS to the rats on the integrity of the pancreas, on the ability of isolated pancreatic acini to secrete the amylase and on the plasma level of tumor necrosis factor alpha (TNFalpha). The role of NO in the pancreatic resistance to the damage was assessed in animals subjected to repeated administration of LPS. To induce pancreatic damage one group of rats received intraperitoneal (i.p.) injection of LPS (from E. coli) every day during 5 consecutive days (10 mg/kg--day). Another groups of animals were given N(G)-nitro-L-arginine (L-NNA), an inhibitor of NO synthase (NOS) (20 mg/kg i.p.) alone or in combination with L-arginine (100 mg/kg i.p.), 30 min prior to each LPS injection. Plasma level of TNFalpha was determined by ELISA kit. Repeated administration of LPS produced mild pancreatic inflammation that was most pronounced at day 5 of LPS treatment and manifested as edema, neutrophil infiltration and hemorrhage of the pancreas. The survival rate after 5 days treatment with LPS was 87.5%. Pancreatic weight, plasma levels of TNFalpha and amylase, pancreatic blood flow (PBF) and NO generation by pancreatic acini were markedly increased in rats subjected to repeated administration of LPS whereas the amylase response of isolated pancreatic acini to pancreatic secretagogues was significantly attenuated. Suppression of NOS by L-NNA resulted in a dramatic increase in the mortality of the animals reaching 50% and significantly increased inflammatory changes in the pancreatic tissue, decreased PBF, abolished the ability of pancreatic acini to release NO and to secrete amylase. Pancreatic weight and plasma levels of amylase and TNFalpha significantly increased in the group of rats treated with combination of LPS+L-NNA as compared to the animals received LPS alone. Addition of L-arginine to L-NNA+LPS administration reversed all harmful effects produced by L-NNA in the pancreas. We conclude that repeated administration of high doses of bacterial LPS to the rats could induce pancreatic tissue damage by itself, however, it is not able to produce severe pancreatitis. Suppression of NO generation significantly aggravates the pancreatic lesion produced by LPS leading to the dramatic mortality in treated rats. The rise of plasma level of TNFalpha corresponds to the severity of pancreatic inflammation.
authors.affiliation: Department of Physiology, Jagiellonian University, Kraków, Poland.
authors.forename: J
authors.initials: J
authors.lastname: Jaworek
authors.forename: B
authors.initials: B
authors.lastname: Jachimczak
authors.forename: J
authors.initials: J
authors.lastname: Bonior
authors.forename: M
authors.initials: M
authors.lastname: Kot
authors.forename: R
authors.initials: R
authors.lastname: Tomaszewska
authors.forename: E
authors.initials: E
authors.lastname: Karczewska
authors.forename: J
authors.initials: J
authors.lastname: Stachura
authors.forename: W
authors.initials: W
authors.lastname: Pawlik
authors.forename: S J
authors.initials: SJ
authors.lastname: Konturek
mesh_terms: D000208:Acute Disease; D000681:Amylases / Q000097:blood; D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008070:Lipopolysaccharides; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D019335:Nitroarginine / Q000494:pharmacology; D009929:Organ Size; D010179:Pancreas / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D019335:Nitroarginine; D009569:Nitric Oxide; D000681:Amylases