CHEMOKINES IN THE PATHOGENESIS OF ASTHMA

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Chemokines in the Pathogenesis of Asthma. Asthma represents a serious health problem particularly for inner city children. Recent studies have identified that many of the asthmatic attacks are triggered by exposure to cockroach allergens however, the mediators within the lung that dictate progression of disease have still not been fully defined. While many potential mediators have been examined previously, asthma still exacts a toll on the patients. More specific, targeted therapy has the potential to improve the treatment of asthma by identifying those mediators directly responsible for the pathogenesis of the disease. This project will test the hypothesis that asthma-like pulmonary injury is mediated by the local production of chemokines. Chemokines are small molecular weight peptides which induce the chemotaxis and recruitment of inflammatory cells. They are powerful mediators with long lasting and potent biological activities. Our first specific aim will determine the acute and chronic pulmonary inflammation that develops after direct injection of the chemokines into the lung. The assessment of the injury will include histologic and morphometric analysis as well as an assessment of the innervation of the airways. The second specific aim will develop a mouse model of asthma-like pulmonary inflammation in response to cockroach allergens. This model will be established by locating households with high levels of cockroach allergens (done in conjunction with the other two research projects) and using this material to immunize the mice. The mice will be challenged by exposure to aerosols containing the dust with the cockroach allergens and the pulmonary injury carefully quantitated including an analysis of innervation of the airways. Our third specific aim will investigate the biochemical pathways responsible for the upregulation of the chemokines in cells sensitized and then challenged with cockroach allergens. We will focus on reactive oxygen and reactive nitrogen intermediates since they have been demonstrated to increased the transcription of chemokines. Our last specific aim will rigorously test the central hypothesis that chemokines are important in the pathogenesis of asthma. This will be tested by blocking the biological activity of the chemokines with specific neutralizing antibodies and determining if there is a reduction in the pulmonary inflammation induced by repeated exposures to the cockroach allergens. Successful completion of our project will both delineate the underlying mechanisms of disease and identify potential novel targets for intervention.