A neutrophil elastase inhibitor, sivelestat, reduces lung injury following endotoxin-induced shock in rats by inhibiting HMGB1.

Abstract

Neutrophil elastase (NE) plays an important role in the progression of acute lung injury (ALI). Sivelestat sodium hydrate (Sivelestat) is a highly specific synthetic inhibitor of NE. High mobility group box 1 (HMGB1) is one of the key mediators in the development of sepsis. The aim of this study was to evaluate the effect of sivelestat and to determine whether it can reduce lipopolysaccharide (LPS)-induced acute lung injury in rats. Rats were randomly divided into a negative control group, an LPS-induced sepsis group, and a group treated with sivelestat prior to LPS administration. Animals in the sivelestat group received a bolus of 10 mg/kg of sivelestat injected into the intraperitoneal cavity before the LPS treatment. Furthermore, rats were administered sivelestat at 0, 1, 3, and 6 h following LPS treatment. We measured cytokine and HMGB1 levels in the serum after the induction of sepsis. In addition, we observed histopathology, wet/dry weight ratio, inducible nitric oxide synthase and HMGB1 expression in the lung tissue. Lung histopathology was significantly improved in the sivelestat group compared to the LPS group. Serum and pulmonary HMGB1 levels were lower over time among sivelestat-treated animals. Furthermore, inhibition of NF-kappaB activity was observed with the administration of sivelestat. These results suggest that sivelestat reduces LPS-induced lung injury at least partially by inhibiting inflammation and NF-kappaB activity.

• Authors: Satoshi Hagiwara, Hideo Iwasaka, Kazumi Togo, Takayuki Noguchi
• Journal: Inflammation (Inflammation) Vol. 31 Issue 4 Pg. 227-34 (Aug 2008) ISSN: 0360-3997 [Print] United States
• PMID: 18536984 (Publication Type: Journal Article)

Chemical References

• HMGB1 Protein
• Interleukin-6
• Lipopolysaccharides
• NF-kappa B
• Nitrates
• Nitrites
• Serine Proteinase Inhibitors
• Sulfonamides
• Tumor Necrosis Factor-alpha
• sivelestat
• Leukocyte Elastase
• Glycine

Topics

• Animals
• Glycine (administration & dosage, analogs & derivatives, pharmacology)
• HMGB1 Protein (antagonists & inhibitors, blood)
• Interleukin-6 (blood)
• Leukocyte Elastase (antagonists & inhibitors)
• Lipopolysaccharides (toxicity)
• Lung (drug effects, metabolism, pathology)
• Lung Injury
• Male
• NF-kappa B (antagonists & inhibitors)
• Nitrates (blood)
• Nitrites (blood)
• Rats
• Rats, Wistar
• Serine Proteinase Inhibitors (administration & dosage, pharmacology)
• Shock, Septic (drug therapy, metabolism, pathology)
• Sulfonamides (administration & dosage, pharmacology)
• Tumor Necrosis Factor-alpha (blood)