ROLE OF T LYMPHOCYTES IN AIRWAY HYPERRESPONSIVENESS

气道高反应性（AHR）是哮喘的主要特征，其特征在于气道对各种刺激的过度收缩。AHR发生的潜在机制包括T淋巴细胞的活化和炎性介质的释放，炎性细胞（特别是中性粒细胞）的积聚，以及神经通路的改变。在哮喘患者中，负责的通路可能是特定于某些个体或重叠的，导致考虑在中央和外周气道的反应性差异的相当大的异质性。我们已经使用小鼠模型来研究中枢气道与外周气道的气道功能改变与潜在的发病机制之间的可能关系。在本申请中，我们将追求这些关系，重点是CD8+ T细胞在肺中的独特作用，其可以控制炎症和AHR的发展。我们建议描绘的途径，CD8依赖性和CD8非依赖性，最终在嗜酸性粒细胞依赖性和嗜酸性粒细胞非依赖性炎症和它们的选择性影响小与大气道功能。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位以及表面活性蛋白功能改变的后果。在最后一个具体的目标，我们将检查炎症，嗜酸性粒细胞和降钙素基因相关肽在发展中的相互作用。总的目的是通过不同的炎症途径将肺淋巴细胞的活化与气道功能改变联系起来，这些炎症途径在气道的不同水平可能不同。该项目与该计划赠款中的其他三个项目有密切联系。所产生的信息不仅对我们理解哮喘的异质性至关重要，而且对考虑不同的治疗方案也至关重要。

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.