AIRWAY INFLAMMATION IN EXERCISE-INDUCED ASTHMA

运动是引发哮喘的重要因素。运动性哮喘的潜在发病机制尚不清楚。热损失或蒸发损失会引发气道内的后续事件，尽管关于每个因素的相对重要性存在相互矛盾的数据。最近的证据表明，运动与其他哮喘触发因素具有共同的病理生理特征，包括急性哮喘反应期间的介质释放，许多个体存在晚期气道反应，以及针对炎症介质的治疗对急性哮喘反应的抑制。我们的假设是，运动性哮喘的发病机制是由于肥大细胞和其他气道细胞在早期支气管收缩反应期间释放介质、细胞因子和趋化因子，随后在哮喘反应晚期炎症细胞浸润气道。具体目的是：1)明确运动引起急性哮喘反应过程中气道和外周血细胞炎症反应的性质；2)确定运动后气道反应是否由炎症细胞浸润气道引起；3)了解预先存在的气道炎症的严重程度与运动后气道反应的发展之间的关系；4)确定白三烯拮抗剂和皮质类固醇在运动性哮喘晚期管理中的作用。实验方法将评估特定介质（组胺、胰蛋白酶、白三烯）、Th2细胞因子（IL-3、IL-4、IL-5、IL-13）和促嗜酸性粒细胞和中性粒细胞趋化因子（MCP-3、RANTES、eotoxin、IL-8）在急性哮喘运动反应发生过程中的释放。哮喘反应晚期的特征是确定运动后哮喘反应晚期气道内炎症细胞（嗜酸性粒细胞、Th2淋巴细胞、中性粒细胞、单核细胞、嗜碱性粒细胞）、Th2细胞因子、嗜酸性粒细胞和中性粒细胞趋化因子以及介质（ECP、MBP、白三烯、组胺、胰蛋白酶）的组成。阐明运动性哮喘的机制对哮喘新疗法的开发具有重要意义。

Exercise is an important trigger of asthma. The underlying pathogenesis of exercise-induced asthma remains unclear. Heat loss or evaporative loss triggers ensuing events within the airways, although conflicting data exists about the relative importance of each factor. Recent evidence shows that exercise shares common pathophysiological features with other triggers for asthma including mediator release during the acute asthmatic response, the presence of a late airway response in many individuals, and the inhibition of the acute asthmatic response by therapies targeted at inflammatory mediators. Our hypothesis is that the pathogenesis of exercise-induced asthma is due to mediator, cytokine and chemokine release from mast cells and other airway cells during the early bronchoconstrictor response, which is followed by infiltration of the airways with inflammatory cells, during the late asthmatic response. The specific aims are: 1) to define the nature of the cellular inflammatory response in the airways and peripheral blood during the development of the acute asthmatic response to exercise; 2) to determine if the late airway response to exercise results from infiltration of the airways by inflammatory cells; 3) to understand the relationship between the severity of preexistent airway inflammation and the development of a late airway response to exercise; 4) to determine the role of leukotriene antagonists and corticosteroids in the management of the late phase of exercise-induced asthma. The experimental approach will be to assess the release of specific mediators (histamine, tryptase, leukotrienes), Th2 cytokines (IL-3, IL-4, IL-5, IL-13), and eosinophil and neutrophil promoting chemokines (MCP-3, RANTES, eotoxin, IL-8) during the genesis of the acute asthmatic response to exercise. The late asthmatic response will be characterized by determining the composition of inflammatory cells (Eosinophils, Th2 lymphocytes, Neutrophils, Monocytes, Basophils), Th2 cytokines, eosinophil and neutrophil chemokines, and mediators (ECP, MBP, leukotrienes, histamine, tryptase) within the airways during the late asthmatic response to exercise. Elucidation of the mechanisms of exercise-induced asthma will be important in the development of new therapies for asthma.