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Hepatology. 2009 Sep;50(3):834-43. doi: 10.1002/hep.23052.

Cyclooxygenase-2 prevents fas-induced liver injury through up-regulation of epidermal growth factor receptor.

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  • 1Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.

Abstract

Cyclooxygenase-2 (COX-2)-derived prostaglandins participate in a number of pathophysiological responses such as inflammation, carcinogenesis, and modulation of cell growth and survival. This study used complementary approaches of COX-2 transgenic (Tg) and knockout (KO) mouse models to evaluate the mechanism of COX-2 in Fas-induced hepatocyte apoptosis and liver failure in vivo. We generated Tg mice with targeted expression of COX-2 in the liver by using the albumin promoter-enhancer-driven vector. The COX-2 Tg, COX-2 KO, and wild-type mice were treated with the anti-Fas antibody Jo2 (0.5 microg/g of body weight) for 4 to 6 hours, and the extent of liver injury was assessed by histopathology, serum aminotransferases, TUNEL staining, and caspase activation. The COX-2 Tg mice showed resistance to Fas-induced liver injury in comparison with the wild-type mice; this was reflected by the lower alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, less liver damage, and less hepatocyte apoptosis (P < 0.01). In contrast, the COX-2 KO mice showed significantly higher serum ALT and AST levels, more prominent hepatocyte apoptosis, and higher levels of caspase-8, caspase-9, and caspase-3 activity than the wild-type mice (P < 0.01). The COX-2 Tg livers expressed higher levels of epidermal growth factor receptor (EGFR) than the wild-type controls; the COX-2 KO livers expressed the lowest levels of EGFR. Pretreatment with a COX-2 inhibitor (NS-398) or an EGFR inhibitor (AG1478) exacerbated Jo2-mediated liver injury and hepatocyte apoptosis.

CONCLUSION:

These findings demonstrate that COX-2 prevents Fas-induced hepatocyte apoptosis and liver failure at least in part through up-regulation of EGFR.

PMID:
19585617
[PubMed - indexed for MEDLINE]
PMCID:
PMC2758493
Free PMC Article
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