| Abstrakt: |
Bruck R, Schey R, Aeed H, Hochman A, Genina O, Pines M. A protective effect of pyrrolidine dithiocarbamate in a rat model of liver cirrhosis. Liver International 2004: DOI: 10.1111/j.1478-3231.2004.0900.x. © Blackwell Munksgaard 2004 Nuclear factor kappa B (NF-κB) activation, proinflammatory cytokines, and reactive oxygen species have been implicated as mediators of liver injury and fibrogenesis. We have shown recently that pyrrolidine dithiocarbamate (PDTC), an antioxidant and inhibitor of NF-κB activation, was protective in a rat model of acute liver failure. The aim of the present study was to examine the efficacy of PDTC in a chronic rat model of thioacetamide (TAA)-induced hepatic fibrosis. Liver cirrhosis was induced by intraperitoneal injections of TAA (200 mg/kg) twice weekly for 12 weeks. Two groups of rats also received PDTC (either 20 or 60 mg/kg, i.p. for 12 weeks). TAA administration induced liver cirrhosis, which was inhibited by PDTC in a dose-dependent manner. The histopathologic score of fibrosis, the spleen weight, and hepatic hydroxyproline were significantly lower in the rats treated with TAA+PDTC compared with TAA only ( P<0.001). The hepatic levels of thiobarbituric acid reactive substances and protein carbonyls after 12 weeks of treatment were also lower in the rats treated with TAA+PDTC ( P=0.02 and 0.01, respectively), indicating reduced oxidative stress. Immunohistochemical studies and in situ hybridization demonstrated inhibition of stellate cell (α smooth muscle actin positive) activation, tissue inhibitor of metalloproteinase-2, and collagen α1(I) gene expression in the livers of the PDTC-treated rats. As determined by Northern blot analysis, PDTC had no inhibitory effect on collagen α1(I) gene expression in the rat hepatic stellate cells-T6 cells in vitro. PDTC inhibits the development of liver cirrhosis in TAA-treated rats. The mechanism of action is associated with decreased oxidative stress and hepatic necroinflammation. [ABSTRACT FROM AUTHOR] |
