Hyperventilation with dry air increases airway tone in guinea pigs, rabbits, cats, dogs, monkeys, and humans. The fact that these mammals all exhibit similar responses to hyperpnea with cold-dry air suggests that exercise-induced asthma in humans reflects an enhanced sensitivity to normally occurring phenomena. Experiments with guinea pigs, dogs, and asthmatic humans revealed that hyperpnea with dry air damages the bronchial mucosa, and in animal models, causes bronchovascular hyperpermeability. Although numerous stimuli cause microvascular leakage, little is known about the relationship between hyperpnea-induced mucosal injury, bronchovascular hyperpermeability, and airway hyperactivity. Dry air hyperventilation in canine peripheral airways represents a well controlled titratable local stimulus that results in a very reproducible local response. Thus, this model is ideal for studying the local effects of cooling and drying on peripheral airway structure and function, and will be used to test the general hypothesis that bronchovascular leakage occurs prior to airway narrowing and protects the bronchial mucosa from excessive dehydration. Four specific hypotheses will be evaluated: 1) Bronchovascular leakage and mucosal injury occur during hyperpnea, whereas mediator release and smooth muscle constriction occur after hyperpnea stops, 2) Enhanced bronchovascular leakage before challenge inhibits, but after challenge exacerbates, hyperpnea-induced bronchoconstriction (HIB), 3) Drugs that inhibit HIB do so in part by reducing peripheral airway water loss during hyperpnea, and 4) Airway cooling per se inhibits dry air-induced injury, mediator release, and smooth muscle shortening. In testing these hypotheses, physiological, pharmacological, biochemical, and morphometric techniques will be used to elucidate dry air-induced interactions between mucosal and submucosal cells, smooth muscle, and airway vasculature that occur during and immediately after hyperpnea with dry air. Although caution is required in extrapolating results from animals to humans, the phenomenological similarities in hyperpnea-induced bronchial obstruction that exist between the canine model and asthmatic subjects suggest that understanding dry air-induced responses in dogs will provide new insights concerning the development of chronic airways disease in humans.
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