Protective effects of nafamostat mesilate on liver injury induced by lipopolysaccharide in rats: possible involvement of CD14 and TLR-4 downregulation on Kupffer cells.
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.
Miyaso
Hideaki
H
Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan.
Morimoto
Yoshinori
Y
Ozaki
Michitaka
M
Haga
Sanae
S
Shinoura
Susumu
S
Choda
Yasuhiro
Y
Murata
Hiroshi
H
Katsuno
Goutaro
G
Huda
Kamul
K
Takahashi
Hideo
H
Tanaka
Noriaki
N
Iwagaki
Hiromi
H
D000818:Animals; D001550:Benzamidines; D056486:Chemical and Drug Induced Liver Injury; D015536:Down-Regulation; D006146:Guanidines / Q000494:pharmacology / Q000627:therapeutic use*; D017228:Hepatocyte Growth Factor / Q000097:blood; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000097:blood; D007728:Kupffer Cells / Q000502:physiology*; D018950:Lipopolysaccharide Receptors / Q000502:physiology; D008107:Liver Diseases / Q000188:drug therapy*; D008297:Male; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D051197:Toll-Like Receptor 4 / Q000502:physiology
D001550:Benzamidines; D006146:Guanidines; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D011480:Protease Inhibitors; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D017228:Hepatocyte Growth Factor; C032855:nafamostat