Gliotoxin Stimulates the Apoptosis of Human and Rat Hepatic Stellate Cells and Enhances the Resolution of Liver Fibrosis in Rats (2001)

Author(s): Wright MC; Mann DA; Issa R; Smart DE; Trim N; Murray GI; Primrose JN; Arthur MJ; Iredale JP

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

Abstract: BACKGROUND & AIMS: Hepatic stellate cells (HSCs) play a pivotal role in liver fibrosis and stimulating their apoptosis could be an effective treatment for liver fibrosis. METHODS: Activated HSCs, hepatocytes, and rats with liver fibrosis were treated with gliotoxin. RESULTS: Addition of gliotoxin to activated (alpha-smooth muscle actin positive) rat and human HSCs resulted in morphologic alterations typical of apoptosis. Within 2-3 hours of incubation, caspase 3 activity was markedly induced and caspase inhibitor 1 (Z-VAD-FMK)-sensitive oligonucleosome-length DNA fragments were detectable by gel electrophoresis of low molecular weight DNA. Apoptosis was widespread as judged by fluorescence-activated cell sorter analysis and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining in both rat and human HSCs at concentrations that had no effect on the viability of rat hepatocytes. Gliotoxin treatment significantly reduced the number of activated stellate cells and mean thickness of bridging fibrotic septae in livers from rats treated with carbon tetrachloride. CONCLUSIONS: These data demonstrate proof-of-concept that by up-regulating HSC apoptosis, the extent of fibrosis can be decreased in inflammatory liver injury.

  • Short Title: Gliotoxin stimulates the apoptosis of human and rat hepatic stellate cells and enhances the resolution of liver fibrosis in rats
  • Date: 09-05-2002
  • Journal: Gastroenterology
  • Volume: 121
  • Issue: 3
  • Pages: 685-698
  • Publisher: W.B. Saunders Co.
  • Publication type: Article
  • Bibliographic status: Published

Keywords: Animals Anti-Allergic Agents/pharmacology Apoptosis/*drug effects Calcium/metabolism Carbon Tetrachloride Chlorpromazine/pharmacology Collagen/analysis Cycloheximide/pharmacology Disease Models, Animal Dopamine Antagonists/pharmacology Gliotoxin/chemistry/*pharmacology Humans Immunosuppressive Agents/chemistry/*pharmacology In Situ Nick-End Labeling In Vitro Liver/chemistry/*pathology Liver Cirrhosis/chemically induced/*drug therapy/pathology Male Methapyrilene/pharmacology Mitochondria/metabolism NF-kappa B/metabolism Protein Synthesis Inhibitors/pharmacology Rats Rats, Sprague-Dawley Research Support, Non-U.S. Gov't Tumor Necrosis Factor-alpha/pharmacology


Professor Derek Mann
Prof of Hepatology

Professor Matthew Wright
Professor of Toxicology