PLATELET-ACTIVATING-FACTOR POTENTIATES PROTAMINE-INDUCED LUNG EDEMA - ROLE OF EICOSANOIDS

Platelet-activating factor (PAF) is a cell membrane-derived ether lipid that plays an important role in acute lung vascular injury. We recently reported that PAF potentiates protamine-induced lung edema by enhancing pulmonary venoconstriction. As PAF is known to stimulate lung eicosanoid synthesis, we investigated the role of peptidoleukotrienes and other eicosanoids in this priming effect of PAF. Addition of PAF (1.6 nM), followed 10 min later by protamine (50 mu g/ml), to perfusate of salt solution-perfused rat lungs resulted in marked arterial and venous constrictions and severe lung edema. Lung tissue thromboxane B-2, 6-keto-prostaglandin F-1 alpha and leukotriene C-4 (LTC(4)) were markedly elevated 20 min after PAF/protamine, Pretreatment of the lungs with AA-861, a specific 5-lipoxygenase inhibitor, blocked PAF/protamine-induced leukotriene synthesis, arterial and venous constrictions, and lung edema. In addition, injection of LTC(4) (1 mu g) markedly potentiated protamine-induced arterial and venous constrictions and caused lung edema similar to PAF/protamine. Indomethacin, a specific cyclooxygenase inhibitor, also reduced the vasoconstrictive and edemagenic responses to PAF-protamine. However, the pulmonary edema after LTC(4)/protamine was not blocked by indomethacin. In separate experiments, infusion of this ''priming'' dose of PAF into isolated perfused lungs induced LTC(4) synthesis and augmented lung thromboxane A(2) synthesis after arachidonic acid infusion. We conclude that both cyclooxygenase and lipoxygenase products of arachidonic acid metabolism are involved in PAF-induced potentiation of protamine lung edema.