Airway responsiveness in transgenic mice overexpressing platelet-activating factor receptor. Roles of thromboxanes and leukotrienes.

Platelet-activating factor (PAF) is a potent proinflammatory compound potentially involved in the pathogenesis of inflammatory disorders, including bronchial asthma. To elucidate the pathophysiologic roles of PAF in bronchial asthma, we studied airway responsiveness in transgenic mice overexpressing PAF receptor. In the transgenic mice, PAF-induced airway smooth muscle contraction was demonstrated by physiologic and morphometric analyses, whereas there was no significant response in the littermate control group. The PAF-elicited bronchoconstriction in the transgenic mice was significantly reduced not only by a PAF receptor antagonist (WEB-2086) but also by a thromboxane synthesis inhibitor (indomethacin or ozagrel), an inhibitor of 5-lipoxygenase-activating protein (MK-886), or a cysteinyl leukotriene (LT) antagonist (pranlukast). LTB4 receptor antagonist (ONO-4057), however, had no effect on the PAF-induced responses. The transgenic mice showed a bronchial hyperreactivity to methacholine challenge, which was also inhibited by pretreatment with either thromboxane synthesis inhibitor or cysteinyl LT antagonist. These observations suggest that both thromboxane A2 and cysteinyl LTs (LTC4, LTD4, and LTE4) are involved in the bronchial responses to PAF or cholinergic stimulus in mice. The transgenic mice overexpressing PAF receptor may provide an appropriate model to study various PAF-related lung diseases, including bronchial asthma.