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Transgenic Expression of Cyclooxygenase-2 in Hepatocytes Accelerates Endotoxin-Induced Acute Liver Failure¹

Chang Han^2,*, Guiying Li^*,, Kyu Lim^*,, Marie C. DeFrances^*, Chandrashekhar R. Gandhi^* and Tong Wu^2,*

^* Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, Jilin University, Jilin, China; and Department of Biochemistry, College of Medicine, Chungnam National University, Daejeon, Korea

Bacterial LPS (endotoxin) is implicated in the pathogenesis of acute liver failure and several chronic inflammatory liver diseases. To evaluate the effect of hepatocyte cyclooxygenase (COX)-2 in LPS-induced liver injury, we generated transgenic mice with targeted expression of COX-2 in the liver by using the albumin promoter-enhancer driven vector and the animals produced were subjected to a standard experimental protocol of LPS-induced acute fulminant hepatic failure (i.p. injection of low dose of LPS in combination with D-galactosamine (D-GalN)). The COX-2 transgenic mice exhibited earlier mortality, higher serum aspartate aminotransferase and alanine aminotransferase levels and more prominent liver tissue damage (parenchymal hemorrhage, neutrophilic inflammation, hepatocyte apoptosis, and necrosis) than wild-type mice. Western blot analysis of the liver tissues showed that LPS/D-GalN treatment for 4 h induced much higher cleavage of poly(ADP-ribose) polymerase, caspase-3, and caspase-9 in COX-2 transgenic mice than in wild-type mice. Increased hepatic expression of JNK-2 in COX-2 transgenic mice suggest that up-regulation of JNK-2 may represent a potential mechanism for COX-2-mediated exacerbation of liver injury. Blocking the prostaglandin receptor, EP₁, prevented LPS/D-GalN-induced liver injury and hepatocyte apoptosis in COX-2 transgenic mice. Accordingly, the mice with genetic ablation of EP₁ showed less LPS/D-GalN-induced liver damage and less hepatocyte apoptosis with prolonged survival when compared with the wild-type mice. These findings demonstrate that COX-2 and its downstream prostaglandin receptor EP₁ signaling pathway accelerates LPS-induced liver injury. Therefore, blocking COX-2-EP₁ pathway may represent a potential approach for amelioration of LPS-induced liver injury.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by R01 Grants CA106280, CA102325 and DK077776 (to T.W.) and DK054411 (to C.R.G.) from the National Institutes of Health. C.H. is the recipient of the Cancer Research and Prevention Foundation Scholar Award. G.L. is supported in part by the China Scholarship Council.

² Address correspondence and reprint requests to Dr. Chang Han or Dr. Tong Wu, Department of Pathology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213. E-mail address: changhan{at}pitt.edu or wut{at}upmc.edu

³ Abbreviations used in this paper: COX, cyclooxygenase; PARP, poly(ADP-ribose) polymerase; D-GalN, D-galactosamine; AST, aspartate aminotransferase; ALT, alanine aminotransferase.