The long term objectives of this proposal are to explore the physiological, pathological, immunological, cellular, and biochemical influences that control and modulate airway responses in humans in health and disease. To achieve these goals 3 sets of investigations are proposed. In the first, the pathologic features in airway biopsies from atopic and non-atopic asthmatics will be compared with the subjects' disease activity, airway reactivity, immunologic profile, and the cellular and mediator content in bronchoalveolar lavage fluid. The macrophages harvested from the lavage will also be investigated for their ability to produce inflammatory mediators and cytokines in response to various stimuli. The data from all of these investigations will then be compared with those found in similar experiments in atopic subjects without asthma, bronchitics with heightened airway reactivity and normal subjects. In the second set of studies, the mechanisms underlying nocturnal fluctuations in lung function is asthmatics will be investigated by comparing the circadian changes that develop in pulmonary mechanics, catecholamines, inflammatory mediators, and cortisol. Normal subjects and atopic non-asthmatics without nocturnal difficulties will serve as controls. The third group of experiments are designed to define the role of the airway microcirculation in airway responsiveness. In these studies we will examine if vascular hyperemia and edema contribute to the obstructive response to thermal stimuli in conditions other than asthma. To achieve this end, intraairway temperatures will be directly recorded during maneuvers designed to alter the rate of airway cooling and rewarming.
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