Fas enhances fibrogenesis in the bile duct ligated mouse: a link between apoptosis and fibrosis.
OBJECTIVE
Hepatocyte apoptosis and fibrosis are both features of liver injury. However, the potential mechanistic link between these 2 processes remains obscure. Our aim was to ascertain if Fas-mediated hepatocyte apoptosis promotes liver fibrogenesis during extrahepatic cholestasis.


METHODS
Wild-type and Fas-deficient lymphoproliferation (lpr) mice underwent bile duct ligation. Liver injury was assessed by quantitating hepatocyte apoptosis with the terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay and determining serum ALT values. mRNA expression was quantitated using real-time polymerase chain reaction technology. Liver fibrosis was assessed by digital image analysis of Sirius red-stained sections.


RESULTS
In 3-day bile duct ligated (BDL) animals, TUNEL-positive hepatocytes and serum ALT values were reduced in lpr versus wild-type animals. Likewise, hepatic mRNA transcripts for alpha-smooth muscle actin and platelet-derived growth factor receptor-beta (initiation phase of stellate cell activation) and transforming growth factor beta1 mRNA, collagen 1alpha, and tissue inhibitor of matrix metalloproteinases (perpetuation phase of stellate cell activation) were also reduced in 3-day BDL wild-type mice compared with lpr mice. Finally, in 3-week BDL mice, immunoreactivity for alpha-smooth muscle actin and Sirius red staining for collagen were significantly less in lpr compared with wild-type animals.


CONCLUSIONS
Fas-mediated hepatocyte injury is mechanistically linked to liver fibrogenesis. These observations suggest that inhibition of Fas-mediated apoptosis may be a therapeutic antifibrogenic strategy in cholestatic liver diseases.
D000199:Actins / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001651:Cholestasis, Extrahepatic / Q000378:metabolism* / Q000473:pathology*; D003094:Collagen / Q000378:metabolism; D003135:Common Bile Duct; D004195:Disease Models, Animal; D005355:Fibrosis; D015870:Gene Expression / Q000502:physiology; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology*; D008026:Ligation; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000032:analysis; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1; D019014:fas Receptor / Q000378:metabolism*
D000199:Actins; D012333:RNA, Messenger; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D019014:fas Receptor; D003094:Collagen; D020797:Receptor, Platelet-Derived Growth Factor beta