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

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 wildtype mice were treated with the anti-Fas antibody Jo2 (0.5 g/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. (HEPATOLOGY 2009;50: 834-843.)

Curative effects of hydrogen sulfide against acetaminophen-induced hepatotoxicity in mice

“…The hepatoprotective effects of induced COX-2 may be attributable to COX-2-derived PGs that assist liver regeneration (Casado et al, 2001) and inhibit inflammation (Yin et al, 2007). In addition, COX-2 prevents secretory phospholipase A 2 - (Bhave et al, 2008) and fas- (Li et al, 2009) induced liver injury. Accordingly, it is not surprising in our study to observe marked upregulation of hepatocyte COX-2 expression after H 2 S treatment.…”

Celecoxib, a selective cyclooxygenase-2 inhibitor, lowers plasma cholesterol and attenuates hepatic lipid peroxidation during carbon-tetrachloride–associated hepatotoxicity in rats

“…In our own view, the reason for these diverse and conflicting observations may not be unconnected with the complex roles of the COX-2-prostanoid pathway in the pathogenesis and pathophysiology of various liver diseases (Hu, 2003). Li et al (2009) have therefore suggested that given the importance of COX-2-derived PGs in several key aspects of liver pathobiology, including hepatocyte survival, liver regeneration, chronic hepatitis, liver injury, and hepatocarcinogenesis, studies are required to detail the mechanisms of COX-2 and PG actions in different liver diseases and animal models.…”

Transgenic Mice Expressing Cyclooxygenase-2 in Hepatocytes Reveal a Minor Contribution of This Enzyme to Chemical Hepatocarcinogenesis

“…More- Gene expression between Tg and WT mice at 25 weeks after DEN treatment was compared using RTover, in the same model, this COX-2 transgene accelerates endotoxin-induced acute liver failure 29 but prevents Fas-induced liver injury. 30 The expression of hCOX-2 under the transthyretin promoter produced the highest levels of intrahepatic PGE 2 and induced hepatitis in animals more than 12 months of age, characterized by the activation of NF-B, stimulation of the secretion of proinflammatory cytokines, and enhanced macrophage and lymphocyte infiltration. 28 These data are in agreement with the results we observed in aged animals.…”