Mc. Wright et al., Gliotoxin stimulates the apoptosis of human and rat hepatic stellate cellsand enhances the resolution of liver fibrosis in rats, GASTROENTY, 121(3), 2001, pp. 685-698
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.