Gliotoxin stimulates the apoptosis of human and rat hepatic stellate cellsand enhances the resolution of liver fibrosis in rats

Background & Aims: Hepatic stellate cells (HSCs) play a pivotal role in liv er fibrosis and stimulating their apoptosis could be an effective treatment for liver fibrosis. Methods: Activated HSCs, hepatocytes, and rats with li ver fibrosis were treated with gliotoxin. Results; Addition of gliotoxin to activated (a-smooth muscle actin positive) rat and human HSCs resulted in morphologic alterations typical of apoptosis. Within 2-3 hours of incubatio n, caspase 3 activity was markedly induced and caspase inhibitor 1 (Z-VAD-F MK)-sensitive oligonucleosome-length DNA fragments were detectable by gel e lectrophoresis of low molecular weight DNA. Apoptosis was widespread as jud ged by fluorescence-activated cell sorter analysis and terminal deoxynucleo tidyl transferase-mediated deoxyuridine triphosphate nick-end labeling stai ning in both rat and human HSCs at concentrations that had no effect on the viability of rat hepatocytes. Gliotoxin treatment significantly reduced th e number of activated stellate cells and mean thickness of bridging fibroti c septae in livers from rats treated with carbon tetrachloride. Conclusions : These data demonstrate proof-of-concept that by up-regulating HSC apoptos is, the extent of fibrosis can be decreased in inflammatory liver injury.