Asthma is a complex illness involving genetic and environmental interactions targeting the lower airways. Worldwide, its incidence has increased at an alarming rate despite significant therapeutic advances. Although heterogeneity between patients exists at several levels, central to the asthma phenotype airway hyperreponsiveness and inflammation The continuing theme of this program is that immune responses in the chemokines, and eicosanoids released from activated cells, profoundly impact the recruitment, activation, and survival of these inflammatory cells in particular (but not solely) eosinophils, which affect large/central and small/peripheral airway function. As part of these responses, T-cell derived cytokines target glucocorticoid receptors on different cell types, creating a state of corticosteroid resistance. The precise mechanisms by which cytokines alter glucocorticoid responsiveness will be defined. The continuing theme of this program is that immune responses in the lung, triggered by allergen exposure and orchestrated by T cells, result in allergic inflammation. Cytokines, chemokines, and eicosanoids released from activated cells, profoundly impact the recruitment, activation, and survival of these cells, in particular (but not solely) eosinophils, which affect large/central and small/peripheral airway function. As part of these responses, T-cell derived cytokinbes target glucocorticoid receptors on different cell types, creating a state of corticosteroid resistance. The precise mechanisms by which cytokines alter glucocorticoid responsiveness will be defined. Using a murine model of allergen- induced airway inflammation and hyperreponsiveness to address critical issues that cannot early be addressed in humans is a focal point of the program. The role of individual T-cell populations in triggering allergic inflammation will be examined, with emphasis on distinct pathways affecting central vs. peripheral airway function. Calcitonin gene related peptide is depleted during an inflammatory response in the lung. It's role in the maintenance of normal related peptide is depleted during an inflammatory response in the lung. Its role in the maintenance of normal airway tone will be determined. Resolution of eosinophilic inflammation through apoptosis and clearance will be analyzed in vitro, in the murine model, and human tissue. In the model of allergen-induced lung inflammation and in human samples, the formation and activity of lipid- derived chemotactic compounds, 5-oxygenated eicosanoids and their metabolites will be analyzed. These questions will be addressed through use of the combined techniques of biochemistry, experimental pathology, and cellular and molecular biology, interwoven throughout the program and provide a framework for acquiring novel insights into the pathogenesis of asthma and strategies for innovative therapies.
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