Chymase inhibition attenuates lipopolysaccharide/ d-galactosamine-induced acute liver failure in hamsters.
OBJECTIVE
Chymase inhibition has been shown to attenuate matrix metalloproteinase (MMP)-9 and tumor necrosis factor (TNF)-α, both of which are associated with the pathogenesis of acute liver failure (ALF). This study investigated the effects of the chymase inhibitor TY-51469 on lipopolysaccharide (LPS)/D-galactosamine (GalN)-induced ALF in hamsters.


METHODS
TY-51469 (10 or 30 mg/kg) or placebo was administered 1 h before the LPS (160 µg/kg)/GalN (400 mg/kg) injection.


RESULTS
Hepatic chymase activity was significantly increased after the LPS/GalN injection, but the significant increase was dose-dependently and significantly attenuated by treatment with TY-51469. Significant increases in hepatic MMP-9 activity and TNF-α concentration were observed after the LPS/GalN injection, but these increases were also attenuated by treatment with TY-51469. Plasma aspartate aminotransferase and alanine aminotransferase activities were significantly increased after LPS/GalN injection in the placebo-treated group, but the increases were significantly attenuated in the TY-51469-treated group. The area of hepatic necrotic after LPS/GalN injection was significantly reduced by treatment with TY-51469. Treatment with TY-51469 resulted in significant reductions in the hepatic malondialdehyde concentration, mast cell numbers, and gene expressions of interleukin-1β and myeloperoxidase.


CONCLUSIONS
Chymase inhibition could be a useful strategy to attenuate LPS/GalN-induced ALF in hamsters.
Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki, Japan.
Yoshiro
Y
Imai
Shinji
S
Takai
Denan
D
Jin
Koji
K
Komeda
Keitaro
K
Tashiro
Zhong-Lian
ZL
Li
Yoshinori
Y
Otsuki
Haruki
H
Okamura
Michihiro
M
Hayashi
Kazuhisa
K
Uchiyama
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D053818:Chymases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005688:Galactosamine; D015870:Gene Expression; D053583:Interleukin-1beta / Q000235:genetics; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008647:Mesocricetus; D009195:Peroxidase / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D013449:Sulfonamides; C524344:TY 51469; D013876:Thiophenes; D014409:Tumor Necrosis Factor-alpha; D008315:Malondialdehyde; D005688:Galactosamine; D009195:Peroxidase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D053818:Chymases; D020780:Matrix Metalloproteinase 9