Inhibition of cyclooxygenase-2 aggravates secretory phospholipase A2-mediated progression of acute liver injury

Our previous study [Bhave, V. S., Donthamsetty, S., Latendresse, J. R., Muskhelishvili, L., and Mehendale, H. M. 2008-this issue. Secretory phospholipase A2 mediates progression of acute liver injury in the absence of sufficient COX-2. Toxicol Appl Pharmacol] showed that in the absence of sufficient induction and co-presence of cyclooxygenase-2 (COX-2), secretory phospholipase A2 (sPLA2) appearing in the intercellular spaces for cleanup of post-necrotic debris seems to contribute to the progression of toxicant-initiated liver injury, possibly by hydrolysis of membrane phospholipids of hepatocytes in the perinecrotic areas. To further test our hypothesis on the protective role of COX-2, male Fisher-344 rats were administered a selective COX-2 inhibitor, NS-398, and then challenged with a moderately toxic dose of CCl4. This led to a 5-fold increase in the susceptibility of the COX-2 inhibited rats to CCl4 hepatotoxicity and mortality. The CCl4 bioactivating enzyme CYP2E1 protein, CYP2E1 enzyme activity, and the 14CCl4-derived radiolabel covalently bound to the liver proteins were unaffected by the COX-2 inhibitor suggesting that the increased hepatotoxic sensitivity of the COX-2 inhibited rats was not due to higher bioactivation of CCl4. Further investigation showed that this increased mortality was due to higher plasma and hepatic sPLA2 activities, inhibited PGE2 production, and progression of liver injury as compared to the non-intervened rats. In conclusion, inhibition of COX-2 mitigates the tissue protective mechanisms associated with COX-2 induction, which promotes sPLA2-mediated progression of liver injury in an acute liver toxicity model. Because increased sPLA2 activity in the intercellular space is associated with increased progression of injury, and induced COX-2 is associated with hepatoprotection, ratios of hepatic COX-2 and sPLA2 activities may turn out to be a useful tool in predicting the extent of hepatotoxicities. © 2007 Elsevier Inc. All rights reserved