LEUKOTRIENE INHIBITORS ATTENUATE RAT LUNG INJURY INDUCED BY HYDROGEN-PEROXIDE

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Abstract
Reactive O2 species cause lung injury in association with activation of arachidonate metabolism. Because metabolites of the cyclooxygenase pathway did not appear to mediate the injury, the 5-lipoxygenase pathway might be activated and inhibition of the pathway could interfere with the development of the injury. An oxidant lung injury was induced and injury was prevented by inhibiting the lipoxygenase pathway or by blocking leukotriene action. In isolated rat lungs, glucose oxidase added to a glucose-containing, cell-free perfusate was used to produce the injurious O2 species. Lung edema occurred and increased with increasing O2 tension in the inspired air. Light microscopy of the lung showed perivascular fluid cuffs and EM showed endothelial cell damage. Measurements in the lung effluent showed that concentrations of 5-hydroxyeicosatetraenoic acid (5-HETE) and of cyclooxygenase metabolites increased after glucose oxidase administration; BW 755C, U60, 257 and FPL 55712 inhibited the glucose-oxidase-induced lung edema. U60,257 also inhibited the glucose-oxidase-induced increase in 5-HETE without concomitant inhibition of cyclooxygenase metabolites. Glucose oxidase via generation of active O2 species stimulated the lung 5-lipoxygenase pathway and inhibitors of 5-lipoxygenase protected against the oxidant lung injury. The injury occurred in the absence of circulating blood cells and was augmented by increasing the inspired O2 concentration.

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