ROLE OF T LYMPHOCYTES IN AIRWAY HYPERRESPONSIVENESS

气道高反应性(AHR)是哮喘的一个主要特征，其特征是呼吸道对各种刺激过度收缩。AHR发生的机制包括T淋巴细胞的激活和炎性介质的释放，炎性细胞的聚集，特别是中性粒细胞和神经通路的改变。在哮喘患者中，负责的通路可能是特定个体特有的或重叠的，导致考虑到中央和外周气道反应差异的相当大的异质性。我们使用了一个小鼠模型来研究中央和外周气道的气道功能改变与潜在的致病机制之间的可能关系。在目前的应用中，我们将重点关注CD8+T细胞在肺中的独特作用，它可能控制炎症和AHR的发展。我们建议描绘CD8依赖和CD8非依赖的途径，最终导致嗜酸性粒细胞依赖和非嗜酸性粒细胞依赖的炎症，以及它们对小气道和大气道功能的选择性影响。在这些研究中，我们将评估不同炎症细胞选择性募集到炎症肺部部位的后果以及表面活性物质蛋白功能的改变。在最后一个特定目标中，我们将研究炎症、嗜酸性粒细胞和降钙素基因相关肽在发育过程中的相互作用。总体目标是通过不同的炎症途径将肺淋巴细胞的激活与气道功能改变联系起来，这些炎症途径在不同水平的呼吸道可能是不同的。该项目与计划拨款中的其他三个项目有密切的联系。产生的信息不仅对我们理解哮喘的异质性至关重要，而且对于考虑不同的治疗方案也是至关重要的。

Airway hyperreponsiveness (AHR) is a predominant feature of asthma and is characterized by the airways constricting excessively in response to a variety of stimuli. Mechanisms underlying the development of AHR include the activation of T lymphocytes and the release of inflammatory mediators, the accumulation of inflammatory cells, particularly and neutrophils, and altered neural pathways. Among asthmatics, the path the pathways responsible may be particular to certain individuals or overlap, resulting in considering in considerable heterogeneity of differences in responsiveness in both central and peripheral airways. We have used a murine model to investigate possible relationships between altered airway function in central vs. peripheral airways and underlying pathogenetic mechanisms. In the present application, we will pursue these relationships focusing on a unique role for CD8+ T cells in the lung which may control inflammation and the development of AHR. We propose to delineate the pathways, both CD8-dependent and CD8- independent, culminating in eosinophil-dependent and eosinophil- independent inflammation and their selective effects on small vs. large airway function. In these studies, we will assess the consequences of selective recruitment of different inflammatory ells to sites in the inflamed lung as well as alterations in surfactant protein function. In the last specific aim, we will examine the interactions between inflammation, eosinophils and calcitonin gene-related peptide in the development. The overall obj4ective is to link the activation of lung lymphocytes with altered airway function via distinct inflammatory pathways that may differ at different levels of the airways. This project has close ties to the other three projects in the program grant. The information generated will not only be critical to our understanding of the heterogeneity of asthma but also for consideration of different therapeutic alternatives.