Therapeutic time-window of a group IIA phospholipase A(2) inhibitor in rabbit acute lung injury: Correlation with lung surfactant protection

Objective: We attempted to determine whether group IIA secretory phospholip ase A(2) (sPLA(2)-IIA) blockade after the onset of lung injury exerted ther apeutic efficacy in the treatment of oleic acid (OA)-induced acute lung inj ury by using S-5920/LY315920Na, a novel specific inhibitor of sPLA(2)-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 group s: OA + vehicle groups, intravenous infusion of OA for the first 2 hrs (0.1 mL . kg(-1). hr(-1)) with the addition of vehicle (1 or 2 hrs after OA adm inistration, each n = 9, total 18 rabbits); OA + S-59201/Y315920Na groups, treated identically to the OA control with the addition of S-5920/LY315920N a (1 mg/kg bolus followed by infusion at 0.5 mg . kg(-1). hr(-1)) after OA (1 or 2 hrs after OA administration, each n = 9, total 18 rabbits); saline control groups, treated with saline instead of OA with the addition of vehi cle (1 hr after OA administration, 4 rabbits). Arterial blood gas, lung mec hanics, 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 lun g injury, as estimated by hypoxemia, decreased lung compliance, pulmonary e dema, and vascular permeability. The therapeutic efficacy was similar to th at found in our previous pretreatment study. The treatment after 1 hr drama tically inhibited OA-induced surfactant degradation in the bronchoalveolar lavage fluid (BALF), without affecting the concentrations of thromboxane A( 2), leukotriene B-4, and interleukin-8 in BALF. The degree of surfactant de gradation in BALF paralleled well with the severity of the lung injury. Fur thermore, recombinant human sPLA(2)-IIA reproduced the similar hydrolysis p attern of isolated surfactant in vitro, which was inhibited by S-5920/ LY31 5920Na. Conclusions:Our results indicate that therapeutic blockade of sPLA(2)-IIA a meliorated lung dysfunction via protection of surfactant degradation in an animal model of acute lung injury, and they suggest a new strategy in treat ing clinical acute lung injury.