Protective action of lipopolysaccharides in rat caerulein-induced pancreatitis: Role of nitric oxide

Lipopolysaccharides (LPS), the component of the cell wall of gram-negative bacteria, have been implicated in the pathogenesis of acute pancreatitis, b ut the mechanism of their action on the pancreas has not been fully explore d. The aim of this study was to investigate the effects of various doses of LPS on the integrity of intact pancreas and that involved in acute caerule in-induced pancreatitis (CIP) in the rat and to compare these effects with those of nitric oxide (NO) donor, S-nitrose-acetyl-penicillamine (SNAP). Th e expression of constitutive NO synthase (cNOS) and inducible NO synthase ( iNOS) mRNA was also examined in the isolated pancreatic acini obtained from the inflamed pancreas of rats treated with LPS. CIP was produced by subcut aneous (s.c.) infusion of caerulein (5 mu g/kg h for 5 h) to conscious rats . Bolus injections of various doses of LPS (0.1, 1, 10, 20 or 40 mg/kg) or SNAP (1.5, 3 or 6 mg/kg) were made intraperitoneally (i.p.) either alone or 30 min prior to s.c. infusion of caerulein to induce CIP. Infusion of caer ulein produced acute pancreatitis confirmed by histological examination and manifested by an increase of pancreatic mass (by about 200%). Blood levels of amylase and lipase were augmented by 400 and 800% respectively, whereas the pancreatic blood flow (PBF) was decreased by 50% in rats with CIP. Inj ection of low doses of LPS (0.1-1 mg/kg i.p.) or SNAP (1.5-3 mg/kg i.p.) 30 min prior to caerulein infusion reversed the harmful effects of pancreatic overstimulation with caerulein and reduced significantly the histological manifestations of CIP such as edema, neutrophil infiltration and vacuolizat ion of the acinar cells. These protective effects of low doses of LPS pretr eatment on the pancreas were completely antagonized by the suppression of t he activity of NO synthase (NOS) with NG-nitro-L-arginine (L-NNA) applied ( 20 mg/ kg i.p.) 15 min prior to the LPS injection. Combination of L-arginin e (100 mg/kg i.p.), a substrate for NOS, with L-NNA given prior to low dose s of LPS, restored the LPS-induced protection of the pancreas in rats with CIP. In contrast, higher doses of LPS (20-40 mg/kg i.p.) or SNAP (6 mg/kg i .p.), which produced a significant fall of the PBF, did not protect the pan creas against CIP. Administration of various doses of LPS to rats with CIP resulted in significant and dose-dependent stimulation of NO biosynthesis i n the isolated acini obtained from the pancreas of these animals. LPS enhan ced the expression of both cNOS and iNOS in the pancreatic acini obtained f rom rats subjected to CIP. The signal for cNOS mRNA was detected in all sam ples, reaching peak at the protective dose of LPS (1 mg/kg i.p.), while iNO S was overexpressed only at the highest doses of LPS that failed to exhibit the protective activity. We conclude that the pretreatment with low doses of LPS protects the pancreas against the damage provoked by CIP and this ef fect could be attributed, at least in part, to the activation of L-arginine -NO system in the pancreas. Copyright (C) 2000 S. Karger AG, Basel.