Rapamycin inhibits hepatic stellate cell proliferation in vitro and limitsfibrogenesis in an in vivo model of liver fibrosis

Background & Aims: The accelerated course of hepatic fibrosis that occurs i n some patients after liver transplantation is a major clinical problem. Th is response may be caused by the antirejection therapeutics, and in an earl ier report we showed that FK-506 enhanced the fibrogenic process in in vivo and in vitro models of liver fibrosis. In the present study, the aim was t o determine whether a new immunosuppressive agent, rapamycin, enhances or i nhibits liver fibrosis. Methods: Effects of rapamycin were investigated in a carbon tetrachloride model of hepatic fibrosis in rats and on hepatic ste llate proliferation in vitro. Results: Rapamycin inhibited extracellular ma trix deposition in the rat model of fibrogenesis as determined by histologi cal analysis, collagen content, messenger RNA levels of procollagen and tra nsforming growth factor pi, and tissue transglutaminase activity. Moreover, rapamycin decreased platelet growth factor-induced proliferation of hepati c stellate cells. Conclusions: These findings indicate that the new antirej ection agent rapamycin inhibits hepatic fibrosis and thus may become a valu able addition to the immunosuppression armamentarium.