Cytosolic phospholipase A2 inhibition attenuates ischemia-reperfusion injury in an isolated rat lung model.

Background. Arachidonic acid metabolites and platelet-activating factor (PAF) are potentially involved in ischemia-reperfusion (IR) lung injury. A key enzyme regulating their metabolism is cytosolic phospholipase A 2 (cPLA 2 ). Arachidonyl trifluoromethyl ketone (AACOCF 3 ) is reported to be a potent cPLA 2 inhibitor. In the present study, we hypothesized that pharmacological inhibition of cPLA 2 might ameliorate IR lung injury. Methods. To test the hypothesis, we examined the effects of AACOCF 3 in an isolated rat lung model. Three groups were defined (n=6, each): in the vehicle group, lungs were perfused for 2 hours without an ischemic period. In the ischemic groups, 20 mg/kg of AACOCF 3 (AACOCF 3 group) or saline (control group) was i.v. administered 15 min before lung harvest. Lungs were flushed with LPD solution, cold-stored 18 hours, and reperfused for 2 hours. Results. IR increased cPLA 2 activity mainly via alveolar macrophages, sPLA 2 activity, thromboxane and leukotriene formation, and the expression of PAF receptor, whereas AACOCF3 treatment significantly reduced all of these. Compared to the vehicle group, the wet-to-dry ratio, proteins in BAL, and MPO activity increased significantly by twofold, fourfold, and threefold, respectively. Furthermore, the PO 2 dropped from 615.7±31.2 to 452.1±30.9 mmHg at the end of reperfusion (P<0.001). AACOCF 3 treatment maintained the PO 2 at a level similar to the vehicle group throughout reperfusion and reduced significantly the alveolar-capillary leakage, edema formation, and neutrophil extravasation. Conclusion. Pharmacological inhibition of the cPLA 2 cascade decreases bioactive lipid formation and attenuates IR-induced lung injury.