Neutrophil elastase inhibitor (ONO-5046) prevents lung hemorrhage induced by lipopolysaccharide in rat model of cerulein pancreatitis.

Abstract

The protective effects of a neutrophil elastase inhibitor (ONO-5046) on cerulein-induced pancreatitis followed by a septic challenge with intraperitoneal lipopolysaccharide (LPS) were studied in a rat model. Pancreatitis was induced by four intramuscular injections of cerulein (50 micrograms/kg at 1-hr intervals). ONO-5046 was administered by continuous intravenous infusion via the right jugular vein (50 mg/kg/hr, 30 min prior to the first cerulein injection to 20 hr following the last cerulein injection). Significant differences in serum amylase and pancreatic wet weight ratio were not observed between the animals with pancreatitis treated with or without ONO-5046. There was no significant difference in the in vitro tumor necrosis factor-alpha (TNF-alpha) production by peritoneal macrophages from rats with pancreatitis treated with or without ONO-5046. In a second experiment, LPS (10 mg/kg) was administered intraperitoneally as the septic challenge 6 hr following the first cerulein injection. Lung hemorrhage was seen in the animals with pancreatitis 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 hemorrhage in cerulein-induced pancreatitis that follows a septic challenge with LPS can be prevented by the intravenous administration of ONO-5046. Thus there is a significant role for neutrophil elastase in pancreatitis-associated lung injury.

• Authors: L Guo, Y Yamaguchi, S Ikei, H Sugita, M Ogawa
• Journal: Digestive diseases and sciences (Dig Dis Sci) Vol. 40 Issue 10 Pg. 2177-83 (Oct 1995) ISSN: 0163-2116 [Print] United States
• PMID: 7587785 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Lipopolysaccharides
• Serine Proteinase Inhibitors
• Sulfonamides
• Tumor Necrosis Factor-alpha
• Ceruletide
• sivelestat
• Pancreatic Elastase
• Leukocyte Elastase
• Glycine

Topics

• Animals
• Ceruletide
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Glycine (analogs & derivatives, therapeutic use)
• Hemorrhage (chemically induced, pathology, prevention & control)
• Leukocyte Elastase
• Lipopolysaccharides
• Lung Diseases (chemically induced, pathology, prevention & control)
• Macrophages, Peritoneal (drug effects, metabolism)
• Male
• Organ Size (drug effects)
• Pancreas (drug effects, pathology)
• Pancreatic Elastase (antagonists & inhibitors)
• Pancreatitis (chemically induced, complications, metabolism, pathology)
• Rats
• Rats, Wistar
• Serine Proteinase Inhibitors (therapeutic use)
• Sulfonamides (therapeutic use)
• Time Factors
• Tumor Necrosis Factor-alpha (analysis, drug effects)