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, 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 cPLA2 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 PO2 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 PO2 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.