Protective Effect of Neutrophil Elastase Inhibitor (FR136706) in Lethal Acute Liver Failure Induced by D-Galactosamine and Lipopolysaccharide in Rats

Abstract

It has been reported that liver dysfunction with ischemia-reperfusion is improved through selective inhibition of neutrophil elastase (NE) by NE inhibitor. This study was designed to investigate whether NE inhibitor has protective effect in lethal acute liver failure. Rats were treated with D-galactosamine plus lipopolysaccharide (GalN/LPS) to induce acute liver failure. NE inhibitor (FR136706) was administered intravenously before GalN/LPS injection. NE inhibitor increased the survival rate to approximately 80% compared with less than 10% in GalN/LPS-treated rats. NE inhibitor prevented GalN/LPS-induced increase of enzymes and total bilirubin in serum, which are related to liver injury. Histopathological analysis revealed that NE inhibitor decreased the incidence of hepatic apoptosis and neutrophil infiltration in the liver. NE inhibitor inhibited the increased concentration of proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-6 and interferon-gamma), and chemokines (CINC-1 and MIP-2) in serum or liver caused by GalN/LPS, and enhanced anti-inflammatory cytokine, interleukin-10 concentration. NE inhibitor prevented the activation of the transcription factor, nuclear factor-kappa B, induced by GalN/LPS. NE inhibitor also reduced the induction of inducible nitric oxide synthase mRNA and its protein in GalN/LPS-treated liver, and resulted in a decrease in nitric oxide production. These results indicate that NE inhibitor, FR136706, inhibits the induction of a variety of inflammatory mediators such as cytokines, chemokines, and nitric oxide, in part through the inhibition of nuclear factor-kappa B activation, resulting in the prevention of fulminant liver failure.