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Targeted expression of cyclooxygenase‐2 in hepatocytes accelerates LPS‐induced acute liver failure
Author(s) -
Han Chang,
Lim Kyu,
Li Guiying,
Xu Lihong,
Wu Tong
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.465.11
Subject(s) - liver injury , hepatocyte , genetically modified mouse , transgene , fulminant hepatic failure , lipopolysaccharide , medicine , endocrinology , pharmacology , chemistry , liver transplantation , in vitro , biochemistry , transplantation , gene
Bacterial lipopolysaccharide (LPS) is implicated in the pathogenesis of acute liver failure and several chronic inflammatory liver diseases. To evaluate the effect of hepatocyte cyclooxygnese‐2 (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 produced animals were subjected to a standard experimental protocol of LPS‐induced acute fulminant hepatic failure (intraperitoneal injection of low dose of LPS in combination with D‐galactosamine (GalN)). The COX‐2 transgenic mice exhibited earlier mortality, higher serum ALT and AST levels and more prominent liver tissue damage than wild type mice. Western blot analysis of the liver tissues showed that LPS/D‐GalN treatment for 4 hours induced the cleavage of PARP, caspase‐3 and caspase‐9 in COX‐2 transgenic mice but not in wild type mice. Increased hepatic expression of JNK2 in COX‐2 transgenic mice suggests that upregulation of JNK2 may represent a potential mechanism for COX‐2‐mediated exacerbation of liver injury. Blocking the prostaglandin receptor, EP 1 , prevented LPS/D‐GalN‐induced liver injury and hepatocyte apoptosis in COX‐2 transgenic mice. These findings suggest that blocking COX‐2/EP 1 pathway may represent an effective approach for attenuation of LPS‐induced liver injury.