ROLE OF EICOSANOIDS IN AIRWAY HYPERRESPONSIVENESS

气道高反应性是人类哮喘的一个特征

Airway hyperreactivity is a characteristic feature of human asthma and a number of other lung diseases including viral infections, and cigarette smoke induced bronchitis. Recent evidence suggests that activation of endogenous arachidonate metabolism may play an important role in the pathophysiology of airway hyperresponsiveness. The overall goal of this proposal is to investigate the role of cyclooxygenase and lipoxygenase products of arachidonate metabolism in the pathogenesis of airway hyperresponsiveness in a spontaneously occurring model of reversible airway obstruction in the pony. This model of lung disease is unique because equids are the only domestic animals which spontaneously develop recurrent airway obstruction and airway hyperresponsiveness similar to asthma in humans. The specific objectives of this proposal are 1) to determine bronchoalveolar lavage and plasma levels of eicosanoids in ponies with recurrent bronchospasm during clinical remission and following hay dust exposure and in their age and gender-matched controls; 2) to determine the effect of inhibiting phospholipase A2, cyclooxygenase or leukotriene biosynthesis on airway responsiveness, and bronchoalveolar lavage and plasma eicosanoid concentrations in ponies with recurrent bronchospasm during clinical remission and following hay dust exposure and in their age and gender-matched controls; 3) to determine if the effects on airway hyperresponsiveness attributed to endogenous eicosanoids can be duplicated by exogenous administration of the appropriate eicosanoid to principal ponies in disease remission and to their age and gender-matched controls. Dynamic compliance, pulmonary resistance, forced oscillating conductance, functional residual capacity and blood gas tensions will be measured in conscious ponies as indicators of large and small airway caliber while methacholine dose-response curves will be generated to assess airway responsiveness. Plasma and bronchoalveolar lavage fluid will be assayed for eicosanoids using radioimmunoassay and high performance liquid chromatography. These studies will increase understanding of the role of eicosanoids in airway hyperresponsiveness and may lead to improved measures to prevent or treat human asthma.