The long term objective of this proposal is to determine the mechanism by which thermal stimuli (exercise and hyperventilation) produce airway obstruction in asthmatics. The attraction of studying this aspect of asthma is that exercise is a potent, naturally occurring stimulus that is potentially operational in the everyday life of all people with this illness. Thus, if one could unravel the manner in which exercise produces airway obstruction, it may be possible to gain great insights into the pathophysiology of asthma in general and ultimately into mechanisms for its control. The proposed studies are designed to: (1) determine how chronic, and acute or chronic, changes intrathoracic blood volume alter the mechanical consequences that follow hyperventilation and as the inhalation of non-isotonic aerosols affect airway thermodynamics; (2) to evaluate the changes that occur in the osmolarity of the surface fluid in the intrathoracic airways during hyperpnea; (3) to explore the role of airway inflammation and; (4) to ascertain if asthmatics differ from normal in the manner in which they regulate the vascular responses to cold. To achieve the first goal, a group of asthmatics and normal subjects will perform stimulus response curves to isocapnic hyperventilation and hypertonic saline when their plasma volumes are normal, elevated and reduced. The last two states will be achieved by oral salt loading and restriction, respectively. On another occasion they will undergo bronchoscopy with insertion of a thermal probe and will repeat the above challenges, in all particulars, while airstream temperatures are recorded continuously from the mouth to the peripheral airways during hyperpnea and recovery. In the second set of studies the osmolarity of the surface fluid of the trachea will be measured at rest and during hyperpnea in a group of normal and asthmatic subjects by placing a specially designed ion conductivity sensor on the airway surface via bronchoscopy. The third goal will be obtained by measuring autocoid, prostanoid and eicosanoid mediators and cytokines in airway fluid before and after antigen and exercise challenges in asthmatics. The final air will be accomplished by measuring surface blood flow in the fingers with a thermal conductivity sensor in asthmatics and normals before, during and after exposure to cold.
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