NEUTROPHIL ELASTASE INHIBITOR (ONO-5046) PREVENTS LUNG HEMORRHAGE-INDUCED BY LIPOPOLYSACCHARIDE IN RAT MODEL OF CERULEIN PANCREATITIS

The protective effects of a neutrophil elastase inhibitor (ONO-5046) o n cerulein-induced pancreatitis followed by a septic challenge with in traperitoneal lipopolysaccharide (LPS) were studied in a rat model. Pa ncreatitis was induced by four intramuscular injections of cerulein (5 0 mu g/kg at 1-hr intervals). ONO-5046 was administered by continuous intravenous infusion via the right jugular vein (50 mg/kg/hr, 30 min p rior to the first cerulein injection to 20 hr following the last cerul ein injection). Significant differences in serum amylase and pancreati c wet weight ratio were not observed between the animals with pancreat itis treated with or without ONO-5046. There was no significant differ ence in the in vitro tumor necrosis factor-alpha (TNF-alpha) productio n by peritoneal macrophages from rats with pancreatitis treated with o r without ONO-5046. In a second experiment, LPS (10 mg/kg) was adminis tered intraperitoneally as the septic challenge 6 hr following the fir st cerulein injection. Lung hemorrhage was seen in the animals with pa ncreatitis untreated with ONO-5046 24 hr following the first cerulein injection. No significant lung hemorrhage was observed in the animals with pancreatitis treated with ONO-5046 administering 30 min prior to the first cerulein injection. These results suggest that lung hemorrha ge in cerulein-induced pancreatitis that follows a septic challenge wi th LPS can be prevented by the intravenous administration of ONO-5046. Thus there is a significant role for neutrophil elastase in pancreati tis-associated lung injury.