AIRWAY INFLAMMATION IN EXERCISE-INDUCED ASTHMA

运动是哮喘的重要诱因。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在呼吸道内触发随后的事件，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，运动与其他哮喘诱因具有共同的病理生理特征，包括急性哮喘反应过程中介质的释放，许多人存在晚期呼吸道反应，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在早期的支气管收缩反应中，肥大细胞和其他呼吸道细胞释放了介质、细胞因子和趋化因子，随后在哮喘反应的晚期，炎性细胞在呼吸道中渗透。其具体目的是：1)确定运动引起的急性哮喘反应发展过程中呼吸道和外周血中细胞炎症反应的性质；2)确定运动引起的晚期呼吸道反应是否是炎症细胞渗入呼吸道所致；3)了解先前存在的呼吸道炎症的严重程度与运动引起的晚期呼吸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治疗中的作用。实验方法将评估在急性哮喘运动反应的发生过程中，特定的介质(组胺、类胰蛋白酶、白三烯)、Th2细胞因子(IL-3、IL-4、IL-5、IL-13)以及嗜酸性粒细胞和中性粒细胞促进趋化因子(MCP-3、RANTES、eooxin、IL-8)的释放。在运动后哮喘反应过程中，通过测定呼吸道炎症细胞(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、类胰蛋白酶)的组成来确定哮喘晚期反应的特征。阐明运动性哮喘的发病机制对开发新的哮喘治疗方法具有重要意义。

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.