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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL051930-03
Application #
2430733
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1995-07-01
Project End
1999-05-31
Budget Start
1997-06-01
Budget End
1998-05-31
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Freed, Arthur N; McCulloch, Sharron; Meyers, Teresa et al. (2003) Neurokinins modulate hyperventilation-induced bronchoconstriction in canine peripheral airways. Am J Respir Crit Care Med 167:1102-8
Davis, Michael S; Schofield, Brian; Freed, Arthur N (2003) Repeated peripheral airway hyperpnea causes inflammation and remodeling in dogs. Med Sci Sports Exerc 35:608-16
Suzuki, Ryoichi; Freed, Arthur N (2002) Heparin inhibits hyperventilation-induced late-phase hyperreactivity in dogs. Am J Respir Crit Care Med 165:27-33
Davis, Michael S; McCulloch, Sharron; Myers, Teresa et al. (2002) Eicosanoids modulate hyperpnea-induced late phase airway obstruction and hyperreactivity in dogs. Respir Physiol 129:357-65
Suzuki, R; Freed, A N (2000) Hypertonic saline aerosol increases airway reactivity in the canine lung periphery. J Appl Physiol 89:2139-46
Freed, A N; McCulloch, S; Wang, Y (2000) Eicosanoid and muscarinic receptor blockade abolishes hyperventilation-induced bronchoconstriction. J Appl Physiol 89:1949-55
Suzuki, R; Freed, A N (2000) Heparin inhibits eicosanoid metabolism and hyperventilation-induced bronchoconstriction in dogs. Am J Respir Crit Care Med 161:1850-4
Davis, M S; Freed, A N (1999) Repetitive hyperpnoea causes peripheral airway obstruction and eosinophilia. Eur Respir J 14:57-62
Freed, A N; Davis, M S (1999) Hyperventilation with dry air increases airway surface fluid osmolality in canine peripheral airways. Am J Respir Crit Care Med 159:1101-7
Freed, A N; Wang, Y; McCulloch, S et al. (1999) Mucosal injury and eicosanoid kinetics during hyperventilation-induced bronchoconstriction. J Appl Physiol 87:1724-33

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