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

Citation
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
Citations number
36
Categorie Soggetti
Gastroenerology and Hepatology","da verificare
Journal title
GASTROENTEROLOGY
ISSN journal
00165085 → ACNP
Volume
121
Issue
3
Year of publication
2001
Pages
685 - 698
Database
ISI
SICI code
0016-5085(200109)121:3<685:GSTAOH>2.0.ZU;2-U
Abstract
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.