Protective effects of nafamostat mesilate on liver injury induced by lipopolysaccharide in rats: possible involvement of CD14 and TLR-4 downregulation on Kupffer cells

Dig Dis Sci. 2006 Nov;51(11):2007-12. doi: 10.1007/s10620-006-9141-1. Epub 2006 Oct 28.

Abstract

Nafamostat mesilate (NM) is a synthetic protease inhibitor with various biological effects. To determine its effect on liver injury related to sepsis, we investigated the effects of NM on lipopolysaccharide (LPS)-induced liver injury. Wistar rats were allocated into two groups; the NM group underwent intraperitoneal NM administration 30 min before LPS administration, and the control group underwent PBS administration. Serum AST and ALT levels were significantly decreased in NM-treated rats. Reduced levels of TNF-alpha, IL-1beta, and IFN-gamma were observed after LPS administration in NM-treated rats. No significant differences were observed in IL-6 levels between the NM and the control group. In contrast, HGF levels were significantly increased only in control rats. NM treatment decreased protein and mRNA levels of TLR-4 and CD14. Our data suggest that NM treatment has protective effects against LPS-induced hepatotoxicity through downregulation of TLR4 and CD14 in liver, which decreased TNF-alpha, IL-1beta, and IFN-gammaproduction in liver.

MeSH terms

  • Animals
  • Benzamidines
  • Chemical and Drug Induced Liver Injury
  • Down-Regulation
  • Guanidines / pharmacology
  • Guanidines / therapeutic use*
  • Hepatocyte Growth Factor / blood
  • Immunohistochemistry
  • Interleukin-6 / blood
  • Kupffer Cells / physiology*
  • Lipopolysaccharide Receptors / physiology
  • Liver Diseases / drug therapy*
  • Male
  • Protease Inhibitors / pharmacology
  • Protease Inhibitors / therapeutic use*
  • Rats
  • Rats, Wistar
  • Toll-Like Receptor 4 / physiology

Substances

  • Benzamidines
  • Guanidines
  • Interleukin-6
  • Lipopolysaccharide Receptors
  • Protease Inhibitors
  • Tlr4 protein, rat
  • Toll-Like Receptor 4
  • Hepatocyte Growth Factor
  • nafamostat