A broad-spectrum caspase inhibitor blocks concanavalin A-induced hepatitis in mice

被引:15
作者
Kim, KM
Kim, YM
Park, M
Park, K
Chang, HK
Park, TK
Chung, HH
Kang, CY
机构
[1] Seoul Natl Univ, Coll Pharm, Immunol Lab, Seoul 151742, South Korea
[2] Kangweon Natl Univ, Dept Mol & Cellular Biochem, Chunchon, South Korea
[3] LG Chem Ltd, Biotech Res Inst 1, Taejon 305380, South Korea
关键词
fulminant hepatic failure; apoptosis; caspase inhibitor; Con A-induced hepatitis;
D O I
10.1006/clim.2000.4939
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Fulminant hepatic failure (FHF) is a clinical syndrome resulting from massive death of liver cells or sudden and severe impairment of liver function. The causes of FHF are diverse and the overall mortality is very high. Recently, it became clear that apoptosis of hepatocytes is the critical cause of acute hepatic failure in FHF. It is well known that a family of cysteine proteases called caspase is one of the key mediators of the apoptotic pathway. Thus, caspases are attractive potential targets for the treatment of disorders resulting from excessive apoptosis. In this report, we examined the activity of a new caspase inhibitor, Xyz 033 mp. This nonpeptide inhibitor showed broad-spectrum caspase-inhibiting activity and protected primary rat hepatocytes from apoptotic death. In a mouse model of FHF induced by concavalin A (Con A), Xyz 033 mp suppressed elevated AST and ALT and specifically reduced IL-1 beta concentration. Also, Xyz 033 mp rescued mice from lethal experimental hepatitis induced by Con A. In addition, histological examinations indicated that Xyz 033 mp protected hepatocytes from the fatal apoptogenic effect of Con A. These results suggest that Xyz 033 mp may be a candidate therapeutic agent for FHF caused by massive apoptotic death of hepatocytes. (C) 2000 Academic Press.
引用
收藏
页码:221 / 233
页数:13
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