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, in cluding bronchial asthma. To elucidate the pathophysiologic roles of P AF 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 th e littermate control group. The PAF-elicited bronchoconstriction in th e 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 pr otein (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 hyperrea ctivity to methacholine challenge, which was also inhibited by pretrea tment with either thromboxane synthesis inhibitor or cysteinyl LT anta gonist. These observations suggest that both thromboxane A(2) and cyst einyl LTs (LTC4, LTD4, and LTE4) are involved in the bronchial respons es to PAF or cholinergic stimulus in mice. The transgenic mice overexp ressing PAF receptor may provide an appropriate model to study various PAF-related lung diseases, including bronchial asthma.