Gliotoxin non-selectively induces apoptosis in fibrotic and normal livers.
BACKGROUND
Liver fibrosis is the common response to chronic liver injury, ultimately leading to cirrhosis. Several lines of evidence indicate that inducing apoptosis of hepatic stellate cells (HSC) may lead to regression of liver fibrosis. Recently, it was shown that gliotoxin (GTX) induces apoptosis of HSC. However, the clinical use of GTX may be limited because of the lack of cell and tissue specificity, causing a high risk of potentially severe adverse effects. The aim of this study, therefore, was to study the effect of GTX on different cells of the liver.


METHODS
We used normal and fibrotic precision-cut rat liver slices to study the effect of GTX on the various resident liver cell types. In these slices, the complex cell-cell interactions are preserved, which closely mimics the in vivo situation.


RESULTS
GTX exhibited a potent apoptosis-inducing activity in these slices. Both immunohistochemical stainings and real-time mRNA techniques showed that this apoptosis-inducing effect was seen in HSC. However, Kupffer cells and liver endothelial cells were also affected by GTX, whereas hepatocytes were only mildly affected.


CONCLUSIONS
This study indicates that the apoptosis-inducing strategy to treat liver fibrosis has high potential, but it will be necessary to develop an HSC-specific therapy to prevent adverse effects.
Hagens
Werner I
WI
Department of Pharmacokinetics and Drug Delivery, Groningen University Institute for Drug Exploration (GUIDE), University of Groningen, Groningen, The Netherlands. W.I.Hagens@rug.nl
Olinga
Peter
P
Meijer
Dirk K F
DK
Groothuis
Geny M M
GM
Beljaars
Leonie
L
Poelstra
Klaas
K
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D005912:Gliotoxin / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D007728:Kupffer Cells / Q000187:drug effects* / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013047:Specific Pathogen-Free Organisms
D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D005912:Gliotoxin