The preventive effects of heparin-superoxide dismutase on carbon tetrachloride-induced acute liver failure and hepatic fibrosis in mice.

In this study, the effects of heparin-superoxide dismutase conjugate (heparin-SOD) on carbon tetrachloride (CCl4)-induced acute liver failure and hepatic fibrosis were evaluated. To investigate the effects of heparin-SOD on acute liver failure, heparin-SOD was administered to CCl4-treated mice by intravenous injection. Biochemical indicators, such as glutamic oxaloacetic transaminase/glutamic pyruvic transaminase (GOT/GPT), GSH (glutathione), lactate dehydrogenase (LDH), and malondialdehyde (MDA) were determined 24 h after CCl4 treatment. The development of CCl4-induced acute liver failure altered the redox state with a decreased hepatic GSH and increased formation of lipid peroxidative products, which were partially normalized by treatment with heparin-SOD or heparin + SOD. Compared with other groups, the acute liver injury of heparin-SOD group was significantly lessened (reduced activities of GOT/GPT, MDA, and increased activities of GSH). To investigate the effects of heparin-SOD on hepatic fibrosis, heparin-SOD and CCl4 were co-administered by intraperitoneal injection twice a week for 12 weeks. Histological and hepatic hydroxyproline examination revealed that heparin-SOD could significantly prevent the progression of hepatic fibrosis. Moreover, real-time PCR was used to determine transforming growth factor-beta1 (TGF-beta1), metalloproteinase-2 (MMP-2), fibronectin, and collagen-I expression. Significantly, greater fibrosis and TGF-beta1, MMP-2, fibronectin, and collagen-I expression were found in the liver of CCl4-induced mice at the end of 12th week. Heparin-SOD could markedly attenuate the mRNA expression of TGF-beta1, MMP-2, and collagen-I. Western blots of tissue homogenates revealed that the protein expression of TGF-beta1 was substantially reduce also by heparin-SOD treatment. These results demonstrate that administration of heparin-SOD may be useful in the treatment and prevention of acute liver failure and hepatic fibrosis.