Contributions of thromboxane and leukotrienes to PAF-induced impairment of lung function in the rat.

This study was carried out to further clarify the role of eicosanoids in platelet-activating factor (PAF)-induced pulmonary vasoconstriction, bronchoconstriction, and edema formation in the isolated perfused rat lung. Infusion of PAF into the isolated perfused rat lung caused vasoconstriction [mean effective concn (EC50) = 0.88 nmol], caused bronchoconstriction (EC50 = 0.71 nmol), and increased the capillary filtration coefficient (EC50 = 1.4 nmol). Two minutes after injection of 50 nmol PAF, a high thromboxane concentration (3,000 pg/ml) and a low peptidoleukotriene concentration (150 pg/ml) were found in the effluent perfusate. PAF-induced vaso- and bronchoconstriction were unaffected by the non-redox 5-lipoxygenase inhibitor ZM-230,487 but were markedly attenuated by inhibition of cyclooxygenase with acetylsalicylic acid or thromboxane-receptor antagonism with BM-13177. Dual inhibition of cyclooxygenase and 5-lipoxygenase had the most pronounced inhibitory effect on PAF-induced vaso- and bronchoconstriction. None of the inhibitors tested prevented the increase in vascular permeability. We conclude that thromboxane is the major vasoconstrictor and bronchoconstrictor induced by PAF, whereas leukotrienes contribute a significant but minor part in this system. PAF-induced microvascular permeability was not inhibited by blockade of arachidonate metabolism and therefore seems to be mediated by a mechanism independent of eicosanoids.