ROLE OF T LYMPHOCYTES IN AIRWAY HYPERRESPONSIVENESS

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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.