Chymase inhibition attenuates lipopolysaccharide/ d-galactosamine-induced acute liver failure in hamsters.

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. TY-51469 (10 or 30 mg/kg) or placebo was administered 1 h before the LPS (160 µg/kg)/GalN (400 mg/kg) injection. 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. Chymase inhibition could be a useful strategy to attenuate LPS/GalN-induced ALF in hamsters. © 2014 S. Karger AG, Basel.

Citation

Yoshiro Imai, Shinji Takai, Denan Jin, Koji Komeda, Keitaro Tashiro, Zhong-Lian Li, Yoshinori Otsuki, Haruki Okamura, Michihiro Hayashi, Kazuhisa Uchiyama. Chymase inhibition attenuates lipopolysaccharide/ d-galactosamine-induced acute liver failure in hamsters. Pharmacology. 2014;93(1-2):47-56

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PMID: 24457951

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