期刊
JOURNAL OF IMMUNOLOGY
卷 181, 期 11, 页码 8027-8035出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.181.11.8027
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资金
- National Institutes of Health [CA106280, CA102325, DK077776, DK054411]
- Cancer Research and Prevention Foundation Scholar Award
- China Scholarship Council
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 LIS in combination with D-galactosamine (D-GaIN)). 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-GaIN treatment for 4 h induced much higher cleavage of poly(AI)P-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-GaIN-induced liver injury and hepatocyte apoptosis in COX-2 transgenic mice. Accordingly, the mice with genetic ablation of EP1 showed less LPS/D-GaIN-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 Journal of Immunology, 2008, 181: 8027-8035.
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