Na +/H + exchanger inhibitor, FR183998, has protective effect in lethal acute liver failure and prevents iNOS induction in rats

Abstract

Selective inhibition of Na(+)/H(+) exchanger (NHE) improves organ dysfunctions including heart ischemia-reperfusion injury. In vivo and in vitro studies were designed to investigate whether NHE inhibitor has a protective effect in lethal acute liver failure, and if so, what are the mechanisms involved. NHE inhibitor (FR183998) was administered to rats treated with d-galactosamine/lipopolysaccharide (GalN/LPS), or incubated with cultured hepatocytes stimulated by pro-inflammatory cytokine, interleukin (IL)-1beta. FR183998 reduced the increases of pro-inflammatory cytokines such as TNF-alpha, interferon-gamma and CINC-1, but enhanced the anti-inflammatory cytokine, IL-10, leading to the prevention of liver injury and increased survival rate in GalN/LPS-treated animals. FR183998 prevented the activation of transcription factor NF-kappaB induced by GalN/LPS. In vivo and in vitro experiments revealed that FR183998 reduced inducible nitric oxide synthase (iNOS) induction and NO production. Further FR183998 decreased levels of iNOS antisense-transcript in GalN/LPS-treated liver and IL-1beta-treated hepatocytes. FR183998 may reduce a variety of inflammatory mediators such as cytokines and NO in part through the inhibition of NF-kappaB activation, resulting in the prevention of fulminant liver failure, and may inhibit iNOS gene expression at steps of iNOS promoter transactivation and its mRNA stabilization through NF-kappaB and iNOS antisense-transcript, respectively.