INFLAMMATION AIRWAYS REACTIVITY AND ASTHMA

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The primary objectives of this program are to (1) address the immunologic abnormalities present in subjects with asthma that allow inflammatory reactions to develop within their airways, (2) probe the mechanisms through which inflammatory cells alter airways responsiveness, and (3) define the consequences of inflammatory reactions on airway epithelial cells and neural tissue. The central hypotheses are that abnormalities in immune regulation centered around T cells are present in subjects with asthma, and that these T cell abnormalities orchestrate many of the immunopathogenic features associated with asthma. When airways inflammation occurs, cationic proteins from an array of inflammatory cells play a critical role in the alteration of airways responsiveness. In addition, inflammation alters neural control of airways by enhancing release of acetylcholine at prejunctional sites leading to enhanced airways responsiveness. Studies that address these hypotheses will be conducted in man and animal models by a group of investigators representing multiple disciplines and employing the techniques of pulmonary physiology and immunology as well as molecular and cellular biology. In clinical studies, the nature and regulation of T cell recognition of allergenic epitopes in the airways of asthmatics will be examined. As part of these studies, the ability to utilize a fragment of well defined allergen recognized by T cells but not by IgE bound to effector cells will be examined in terms of its role in the therapy of disease. Steroid resistant subjects with asthma will be studied to determine if there is persistent immune activation and inflammation within their airways following steroid therapy. The biochemical and molecular basis for steroid resistance will be examined in freshly isolated peripheral blood mononuclear cells and T cell lines from these patients. In subjects with nocturnal asthma, the hypotheses that they have abnormal control of immune responses as well as altered neural control of airways will be studied. Investigations in animal models will extend questions into areas not easily examined in man. The mechanisms that are operative when airways hyperresponsiveness is seen in the absence of overt airways inflammation will be studied in a rabbit model of C5 fragment-induced sinusitis and a murine model of antigen sensitization induced by aerosol exposure to antigen. Within the murine system, the contribution of allergen-specific and polyclonal IgE to the development of airways hyperresponsiveness will be assessed. The ability of cationic proteins to produce increases in responsiveness alone and when combined with lipid mediators will be addressed in rabbits and rats while mechanisms responsible for enhanced neural and cholinergically mediated responsiveness will be studied in antigen-challenged rabbits and mice. These investigations should provide insight into the mechanisms through which abnormalities of immune regulation alter the function of airway cells and tissues leading to increased airways responsiveness.