Neutrophil elastase inhibitor prevents endotoxin-induced liver injury following experimental partial hepatectomy.
BACKGROUND
During endotoxaemia, neutrophils activated by inflammatory cytokines release reactive oxygen species and neutrophil elastase, resulting in hepatic necrosis and dysfunction. This study investigated the possible mechanism underlying the protective effect of sivelestat, a neutrophil elastase inhibitor, on endotoxin-induced liver injury following partial hepatectomy.


METHODS
Lipopolysaccharide (LPS) was administered intravenously to male Sprague-Dawley rats 48 h after 70 per cent hepatectomy. Sivelestat or normal saline was given intravenously before LPS administration,


RESULTS
Treatment with sivelestat significantly improved the survival rate. Sivelestat prevented increases in the concentration of serum enzymes and total bilirubin related to liver injury. Levels of inflammatory cytokines in serum and liver tissue were significantly lower in the sivelestat-treated group than in the control group. The degree of neutrophil infiltration, necrosis and apoptosis in the remnant liver was significantly decreased in sivelestat-treated rats. Sivelestat pretreatment inhibited the activation of nuclear factor (NF) kappaB, caspase 3 and 8 activities, and cytochrome c release.


CONCLUSIONS
Sivelestat prevents LPS-induced liver injury by inhibition of NF-kappaB activation and apoptosis.
Kwon
A-H
AH
Department of Surgery, Kansai Medical University, 10-15 Fumizono, Moriguchi, Osaka 570-8507, Japan. kon@takii.kmu.ac.jp
Qiu
Z
Z
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D004731:Endotoxins / Q000633:toxicity*; D005998:Glycine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006498:Hepatectomy; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008099:Liver / Q000201:enzymology*; D008107:Liver Diseases / Q000201:enzymology / Q000601:surgery; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*
D004731:Endotoxins; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; C069195:sivelestat; D019272:Leukocyte Elastase; D005998:Glycine