Therapeutic time-window of a group IIA phospholipase A₂ inhibitor in rabbit acute lung injury: Correlation with lung surfactant protection

Objective: We attempted to determine whether group IIA secretory phospholipase A₂ (sPLA₂-IIA) blockade after the onset of lung injury exerted therapeutic efficacy in the treatment of oleic acid (0A)-induced acute lung injury by using S-5920/LY315920Na, a novel specific inhibitor of sPLA₂-IIA, with special interest in the changes of lung surfactant. Design: Prospective animal study. Setting: University laboratory. Subjects: Forty Japanese white rabbits. Interventions: The rabbits, under anesthesia, were endotracheally intubated and mechanically ventilated and then were divided into the following groups: 0A + vehicle groups, intravenous infusion of 0A for the first 2 hrs (0.1 mL·kg^-1·hr^-1) with the addition of vehicle (1 or 2 hrs after 0A administration, each n = 9, total 18 rabbits); 0A + S-5920/LY315920Na groups, treated identically to the 0A control with the addition of S-5920/ LY315920Na (1 mg/kg bolus followed by infusion at 0.5 mg·kg^-1·hr^-1) after 0A (1 or 2 hrs after 0A administration, each n = 9, total 18 rabbits); saline control groups, treated with saline instead of OA with the addition of vehicle (1 hr after 0A administration, 4 rabbits). Arterial blood gas, lung mechanics, lung inflammation, lung surfactant phospholipids, and production of inflammatory mediators in the lung were measured. Measurements and Main Results: Treatment with S-5920/LY315920Na 1 hr after OA infusion, but not 2 hrs after infusion, significantly attenuated the lung injury, as estimated by hypoxemia, decreased lung compliance, pulmonary edema, and vascular permeability. The therapeutic efficacy was similar to that found in our previous pretreatment study. The treatment after 1 hr dramatically inhibited OA-induced surfactant degradation in the bronchoalveolar lavage fluid (BALF), without affecting the concentrations of thromboxane A₂, leukotriene B₄, and interleukin-8 in BALF. The degree of surfactant degradation in BALF paralleled well with the severity of the lung injury. Furthermore, recombinant human sPLA₂-IIA reproduced the simillar hydrolysis pattern of isolated surfactant in vitro, which was inhibited by S-5920/LY315920Na. Conclusions: Our results indicate that therapeutic blockade of sPLA₂-IIA ameliorated lung dysfunction via protection of surfactant degradation in an animal model of acute lung injury, and they suggest a new strategy in treating clinical acute lung injury.