Secretory phospholipase A 2-mediated progression of hepatotoxicity initiated by acetaminophen is exacerbated in the absence of hepatic COX-2
We have previously reported that among the other death proteins, hepatic secretory phospholipase A 2 (sPLA 2) is a leading mediator of progression of liver injury initiated by CCl 4 in rats. The aim of our present study was to test the hypothesis that increased hepatic sPLA 2 released after acetaminophen (APAP) challenge mediates progression of liver injury in wild type (WT) and COX-2 knockout (KO) mice. COX-2 WT and KO mice were administered a normally non lethal dose (400mg/kg) of acetaminophen. The COX-2 KO mice suffered 60% mortality compared to 100% survival of the WT mice, suggesting higher susceptibility of COX-2 KO mice to sPLA 2-mediated progression of acetaminophen hepatotoxicity. Liver injury was significantly higher at later time points in the KO mice compared to the WT mice indicating that the abatement of progression of injury requires the presence of COX-2. This difference in hepatotoxicity was not due to increased bioactivation of acetaminophen as indicated by unchanged cyp2E1 protein and covalently bound 14C-APAP in the livers of KO mice. Hepatic sPLA 2 activity and plasma TNF-a were significantly higher after APAP administration in the KO mice. This was accompanied by a corresponding fall in hepatic PGE 2 and lower compensatory liver regeneration and repair ( 3H-thymidine incorporation) in the KO mice. These results suggest that hindered compensatory tissue repair and poor resolution of inflammation for want of beneficial prostaglandins render the liver very vulnerable to sPLA 2-mediated progression of liver injury. These findings are consistent with the destructive role of sPLA 2 in the progression and expansion of tissue injury as a result of continued hydrolytic breakdown of plasma membrane phospholipids of perinecrotic hepatocytes unless mitigated by sufficient co-induction of COX-2. Â© 2011.
Toxicology and applied pharmacology
Bhave, Vishakha; Donthamsetty, Shashikiran; Latendresse, John R.; Cunningham, Michael L.; and Mehendale, Harihara M., "Secretory phospholipase A 2-mediated progression of hepatotoxicity initiated by acetaminophen is exacerbated in the absence of hepatic COX-2" (2011). PCOM Scholarly Papers. 674.