Halofuginone to prevent and treat thioacetamide-induced liver fibrosis in rats

Hepatic fibrosis is associated with activation of hepatic stellate cells (H SC), the major source of the extracellular matrix (ECM) proteins. The predo minant ECM protein synthesized by the HSC is collagen type I. We evaluated the effect of halofuginone-an inhibitor of collagen synthesis-on thioacetam ide (TAA)-induced liver fibrosis in rats. In the control rats the HSC did n ot express smooth muscle actin, collagen type I gene, or tissue inhibitor o f metalloproteinases-2 (TIMP-2), suggesting that they were in their quiesce nt state. When treated with TAA, the livers displayed large fibrous septa, which were populated by smooth muscle actin-positive cells expressing high levels of the collagen alpha1(I) gene and containing high levels of TIMP-2, all of which are characteristic of advanced fibrosis. Halofuginone given o rally before fibrosis induction prevented the activation of most of the ste llate cells and the remaining cells expressed low levels of collagen alpha1 (I) gene, resulting in low levels of collagen. The level of TIMP-2 was almo st the same as in the control livers. When given to rats with established f ibrosis, halofuginone caused almost complete resolution of the fibrotic con dition. The levels of collagen, collagen alpha1(I) gene expression, TIMP-2 content, and smooth muscle actin-positive cells were as in the control rats . Halofuginone inhibited the proliferation of other cell types of the fibro tic liver in vivo and inhibited collagen production and collagen alpha1(I) gene expression in the SV40-immortalized rat HSC-T6 cells in vitro. These r esults suggest that halofuginone may become an effective and novel mode of therapy in the treatment of liver fibrosis.