Fas enhances fibrogenesis in the bile duct ligated mouse: a link between apoptosis and fibrosis

A Canbay, H Higuchi, SF Bronk, M Taniai, TJ Sebo… - Gastroenterology, 2002 - Elsevier
A Canbay, H Higuchi, SF Bronk, M Taniai, TJ Sebo, GJ Gores
Gastroenterology, 2002Elsevier
Background & Aims: 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 …
Background & Aims
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 α-smooth muscle actin and platelet-derived growth factor receptor-β (initiation phase of stellate cell activation) and transforming growth factor β1 mRNA, collagen 1α, 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 α-smooth muscle actin and Sirius red staining for collagen were significantly less in lpr compared with wild-type animals.
Conclusion
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.
Elsevier