Gliotoxin stimulates the apoptosis of human and rat hepatic stellate cells and enhances the resolution of liver fibrosis in rats.
OBJECTIVE
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.
Wright
M C
MC
Department of Molecular and Cell Biology, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, Scotland. m.c.wright@abdn.ac.uk
Issa
R
R
Smart
D E
DE
Trim
N
N
Murray
G I
GI
Primrose
J N
JN
Arthur
M J
MJ
Iredale
J P
JP
Mann
D A
DA
D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002251:Carbon Tetrachloride; D002746:Chlorpromazine / Q000494:pharmacology; D003094:Collagen / Q000032:analysis; D003513:Cycloheximide / Q000494:pharmacology; D004195:Disease Models, Animal; D018492:Dopamine Antagonists / Q000494:pharmacology; D005912:Gliotoxin / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D008099:Liver / Q000737:chemistry / Q000473:pathology*; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008701:Methapyrilene / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D018926:Anti-Allergic Agents; D018492:Dopamine Antagonists; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D011500:Protein Synthesis Inhibitors; D014409:Tumor Necrosis Factor-alpha; D005912:Gliotoxin; D003094:Collagen; D003513:Cycloheximide; D008701:Methapyrilene; D002251:Carbon Tetrachloride; D002118:Calcium; D002746:Chlorpromazine