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-β1 (TGF-β1), metalloproteinase-2 (MMP-2), fibronectin, and collagen-I expression. Significantly, greater fibrosis and TGF-β1, 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-β1, MMP-2, and collagen-I. Western blots of tissue homogenates revealed that the protein expression of TGF-β1 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.