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Cyclooxygenase‐2 prevents Fas‐induced acute liver failure in mice
Author(s) -
Li Guiying,
Huang Shuo,
Wu Tong
Publication year - 2009
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.23.1_supplement.741.4
Subject(s) - apoptosis , hepatocyte , liver injury , tunel assay , in vivo , protein kinase b , genetically modified mouse , transgene , chemistry , endocrinology , medicine , cancer research , biology , in vitro , biochemistry , microbiology and biotechnology , gene
This study was designed to investigate the role of cyclooxygenase‐2 (COX‐2) in Fas‐induced hepatocyte apoptosis in vivo. We generated transgenic mice with targeted expression of COX‐2 in the liver by using the albumin promoter‐enhancer driven vector. The COX‐2 transgenic (Tg), COX‐2 knockout (KO), and wild type mice were treated with the anti‐Fas antibody Jo2 (0.5 ìg/g body weight) for 4‐6 hours and the extent of liver injury was assessed by histopathology, serum transaminases, TUNEL staining and caspase activation. The COX‐2 Tg mice showed resistance to Fas‐induced liver injury when compared to the wild type mice, as reflected by the lower ALT and 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, 9, 3 activities than the wild type mice (p<0.01). The liver tissues from the COX‐2 Tg mice express higher levels of EGFR and several key molecules of the downstream Akt signaling pathway when compared to the wild type mice. Pretreatment with the COX‐2 inhibitor (NS‐398) or the EGFR inhibitor (AG1478) exacerbated Jo2‐mediated liver injury and hepatocyte apoptosis. These results demonstrate that COX‐2 prevents Fas‐induced hepatocyte apoptosis and liver failure in vivo and the effect is mediated at least in part through EGFR/Akt.