Crucial role of group IIA phospholipase A₂ in oleic acid-induced acute lung injury in rabbits

Group IIA secretory phospholipase A₂ (sPLA₂) has been implicated in a variety of inflammatory diseases including acute lung injury (ALI); however, the role of sPLA₂ in this disorder remains unclear. The aim of the present investigation was to examine the role of this enzyme in a model of ALI induced by oleic acid (OA) in rabbits by testing human group IIA phospholipase A₂ (PLA₂) inhibitor, S-5920/LY315920Na. Experimental groups consisted of a saline control group (n = 8), an OA control group (n = 10) infused intravenously with OA (0.1 ml/kg/h for 2 h), and three groups given OA -S-5920/LY315920Na (three different doses, n = 8, respectively). Infusion of OA provoked pulmonary hemorrhage and edema formation, protein leakage, and massive neutrophil infiltration, resulting in severe hypoxemia and impaired lung compliance. PLA₂ activity was detected in the bronchoalveolar lavage fluid (BALF), but not plasma, which correlated well with severity of lung injury in this model. Pretreatment with S-5920/LY315920Na diminished the OA- induced PLA₂ activity in the BALF and dose-dependently attenuated the previously described lung injury induced by OA, accompanied by protection against lung surfactant degradation and production of thromboxane A₂ (TXA₂) and leukotriene B₄ (LTB₄). S-5920/LY315920Na also inhibited the OA-induced production of interleukin-8 (IL-8), both in plasma and BALF. Thus, sPLA₂ appears to play a key role in OA-induced lung injury, suggesting that the group IIA PLA₂ inhibitor may be a promising agent for patients with acute respiratory distress syndrome (ARDS).