Exercise and hyperventilation with cold dry air (CDA) are important triggers of an asthmatic attack that affects 80% of asthmatics. Bronchoconstriction is also seen after CDA hyperventilation in normal subjects and experimental animals. The major stimuli of exercise asthma and CDA induced bronchospasm are heat and water loss from the airways, resulting in cooling and hypertonicity of the airway lining fluid. As ventilation increases, the trachea becomes a major source of the heat and water required for the conditioning of inspired air. The airway responses to dry air ventilation, and cold and hypertonic stimuli are poorly understood. These responses are important for our understanding of the pathophysiology of asthma, and the normal process of conditioning inspired air. These studies will examine: 1) the responses and 2) die mechanisms of cold and hypertonic stimuli in the trachea of anesthetized dogs, 3) the determinants of water movement from the vasculature into the airstream during the conditioning of air by the trachea, and 4) the movement of macromolecules through the tracheal wall during exposure to hypertonic solutions. In series 1 and 2 the trachea will be isolated in-situ with monitoring of the smooth muscle and vascular tone, and selected epithelial functions. Fluid with temperatures of 38, 26, or 18 degrees C, and osmolalities of 325,900, or 1800 mosM are instilled into the tracheal segment. In particular, qualitative differences to the responses at different osmolalities, and any synergy between the cooling and hypertonic stimuli will be looked for. Series 2 will probe the mechanisms involved in these responses, looking at nervous control and several classes of mediators. In series 3 the in-situ canine trachea will be exposed to 38 degrees C air flowing in one direction at constant flow, with the water content varied from 46 mg/liter (100% saturated), to 0 mg/liter. The water flux into the airstream, temperature, and vascular and smooth muscle responses will be monitored under these well defined conditions. The factors which control the rate of water flux, particularly the role of epithelial ion pumping and the tracheal blood flow , will be examined. In series 4 the movement of macromolecules across the tracheal epithelium and vasculature will be studied in the in-vivo and in-vitro ferret trachea. In particular, markers for epithelial permeability will be looked for, and the behavior of these markers during exposure to hypertonic solutions will be studied. From these studies a clearer picture of the effects of dry air, and its component stimuli, will emerge. This may improve our understanding of asthma, and lead to improvements in our therapy of exercise induced asthma.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Research Manpower Review Committee (MR)
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University of Washington
Schools of Medicine
United States
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