This SCOR Grant proposal has as its underlying premise that the pathogenesis of airway disease such as asthma and chronic bronchitis, and their ultimate control, can best be understood by a detailed examination of the manner in which stimuli that are known to exacerbate these illnesses alter the interplay among the cellular, bio-chemical, and physiologic milieu of the airways. Knowledge must also be gathered as to how the host defends against acute and chronic insults, controls the extent of the reparative processes, and adapts physiologically and clinically over time. To achieve these aims, we propose a series of projects that examine, from multiple perspectives in human subjects and animal and tissue models, the effects of naturally occurring interactive stimuli such as antigen, exercise, cold air, respiratory viruses, cigarette smoke, and air pollutants. Projects 1 and 4 employ measures of pulmonary mechanics, inflammation, and eicosanoid chemistry to comprehensively examine how many of the above exposures disrupt, or alter, the homeostatic influences that control and modulate bronchial and nasal responses in normal humans and those with airway disease. Project 2 compliments Projects 1 and 4 and seeks to determine how air pollutants such as O3, SO2, and NO2 injure the airways, influence epithelial cell function and biochemistry, and alter host responsiveness in animals. Projects 3, 5, and 6 deal with host adaptations and defenses. Project 3 explores whether chronic airway obstruction produces a series of behavioral adaptations in breathing pattern to minimize symptoms, which, in turn, may be significant deleterious effects on ventilation. Project 5 is concerned with the potential of eliciting protective immunity in the respiratory tract to viral infections via primary immunization of the gut. Project 6 deals, in depth, with the role of cellular inflammation in the pathogenesis of airway diseases. Biologic fluids from Projects 1, 2, and 4 will be evaluated for the number and types of polymorphonuclear, and mononuclear cells, and they, plus blood elements, will be assayed for their level of stimulation, capacity to be activated, and ability to release various enzymes and chemotactic factors. This project will also explore the mechanisms by which oxidants and eosinophils, neutrophils, and monocytes damage human and rabbit airway epithelial cell monolayers.
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