protection against fas-induced fulminant hepatic failure in liver specific integrin linked kinase knockout mice防止fas-induced暴发性肝衰竭肝脏特定的整合素连接激酶基因敲除小鼠.pdfVIP

Donthamsetty et al. Comparative Hepatology 2011, 10:11 /content/10/1/11 RESEARCH Open Access Protection against Fas-induced fulminant hepatic failure in liver specific integrin linked kinase knockout mice * Shashikiran Donthamsetty, Wendy M Mars, Anne Orr, Chuanyue Wu and George K Michalopoulos Abstract Background: Programmed cell death or apoptosis is an essential process for tissue homeostasis. Hepatocyte apoptosis is a common mechanism to many forms of liver disease. This study was undertaken to test the role of ILK in hepatocyte survival and response to injury using a Jo-2-induced apoptosis model. Methods: For survival experiments, ILK KO and WT mice received a single intraperitoneal injection of the agonistic anti-Fas monoclonal antibody Jo-2 at the lethal dose (0.4 μg/g body weight) or sublethal dose (0.16 μg/g body weight). For further mechanistic studies sublethal dose of Fas monoclonal antibody was chosen. Results: There was 100% mortality in the WT mice as compared to 50% in the KO mice. We also found that hepatocyte specific ILK KO mice (integrin linked kinase) died much later than WT mice after challenge with a lethal dose of Fas agonist Jo-2. At sublethal dose of Jo-2, there was 20% mortality in KO mice with minimal apoptosis whereas WT mice developed extensive apoptosis and liver injury leading to 70% mortality due to liver failure at 12 h. Proteins known to be associated with cell survival/death were differentially expressed in the 2 groups. In ILK KO mice there was downregulation of proapoptotic genes and upregulation of antiapoptotic genes. Conclusions: Mechanistic insights revealed that pro-survival pathways such as Akt, ERK1/2, and NFkB signaling were upregulated in th