This SCOR grant has as its underlying premise that the pathogenesis of airway diseases such as asthma, chronic bronchitis, and related syndromes, as well as their ultimate control, requires a detailed understanding of the interrelationships among the pathologic, clinical, physiologic, biochemical, and immunobiologic features of each illness. In concert, knowledge must also be gathered as to how the host defends itself against acute and chronic insults, controls the extent of the damage and reparative processes at cellular and organ system levels, and adapts physiologically and clinically over time. To achieve the above aims, we propose a series of experiments that examine these issues from multiple perspectives in human subjects, as well as animal and tissue models, in a highly interrelated and mutually supportive fashion. Project 1 plans to determine the extent to which airway inflammation contributes to the pathogenesis and clinical features of bronchial asthma and related illnesses. It also seeks to explore how the bronchial microcirculation influences airway responses. Project 2 complements Project 1 and focuses on the local cellular regulation of nasal function in health and disease. Project 3 explores whether chronic airway obstruction produces a series of behavioral adaptations in breathing pattern to minimize symptoms, which, in turn, may have significant deleterious effects on ventilation. Project 4 plans to examine cell-cell interactions and will determine how neutrophils and their products become cytotoxic for human airway epithelial cells under different conditions of growth and differentiation. This project will also examine if, and how, epithelial cells and their biochemical products influence neutrophil function. Project 5 deals with the basic biology of leukocyte adhesion and migration and the role that these factors play in the production of airway disease. Project 6 is concerned with the biochemistry and molecular biology of smooth muscle contraction. Project 7 plans to explore the potential of eliciting protective immunity in the respiratory tract to viral infections via primary immunization of the gut. Mucosal adjuvants, vector vaccines with salmonella, and IgA monoclonal antibodies against Sendai virus are to be used to accomplish this task. Biologic fluids from Projects 1, 2, 4, 5, and 7 will be analyzed in Core B for eicosanoid, prostanoid, and cytokine content.
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