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

Hironori Tanaka, Yoichiro Uchida, Masaki Kaibori, Takeshi Hijikawa, Morihiko Ishizaki, Masanori Yamada, Kosuke Matsui, Takashi Ozaki, Katsuji Tokuhara, Yasuo Kamiyama, Mikio Nishizawa, Seiji Ito, Tadayoshi Okumura

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)

Abstract

Background/Aims: 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. Methods: 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)-1β. Results: FR183998 reduced the increases of pro-inflammatory cytokines such as TNF-α, interferon-γ 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-κB 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-1β-treated hepatocytes. Conclusions: FR183998 may reduce a variety of inflammatory mediators such as cytokines and NO in part through the inhibition of NF-κB 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-κB and iNOS antisense-transcript, respectively.

Original languageEnglish
Pages (from-to)289-299
Number of pages11
JournalJournal of Hepatology
Volume48
Issue number2
DOIs
Publication statusPublished - 02-2008
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Hepatology

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