Neutrophil elastase inhibitor prevents endotoxin-induced liver injury following experimental partial hepatectomy

Abstract

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) κB, caspase 3 and 8 activities, and cytochrome c release. Conclusion: Sivelestat prevents LPS-induced liver injury by inhibition of NF-κB activation and apoptosis. Copyright © 2007 British Journal of Surgery Society Ltd Published by John Wiley & Sons Ltd.