Numerous studies have related global respiratory heat and/or water loss to the degree of bronchoconstriction induced in asthmatics by isocapnic hyperpnea of dry air. While these have provided insight into the precipitation of airways response, the detailed sequence of events stemming from conditioning of inspired air to airflow obstruction in hyperpnea-induced bronchoconstriction (HIB) remains unknown. In this application, experiments are proposed to examine three aspects of this pathophysiological sequence, at various sites along the bronchial tree: (i) the """"""""stimulus"""""""" - i.e., changes in local airway wall temperature, hydration, or osmolarity which result from the balance between local heat/water losses and the efficacies of replenishing heat or water sources; (ii) the """"""""response"""""""" - i.e., the severity of local airway narrowing precipitated by local or distant stimuli; and (iii) the """"""""mechanism"""""""" of the response - i.e., the roles of various mediators in effecting local hyperpnea-related bronchoconstriction. To achieve these broad objectives, three sets of experiments are proposed: (I) The investigators will directly measure airway mucosal temperature, hydration, and osmolarity, as well as local heat and water losses, at various sites along the respiratory path, while varying inspired gas conditions and physical properties, breathing pattern, and bronchial arterial or pulmonary arterial blood flow in sheep. (II) The investigators will identify the axial distribution of bronchoconstriction induced by isocapnic dry air hyperpnea in guinea pigs, in order to deduce stimulus-response relationships at various sites along the airways, using measurements of lung mechanics and tantalum oxide (Ta2O5) bronchography. (III) The importance of 3 potential mechanisms of guinea pig hyperpnea-induced bronchoconstriction (mast cell mediator secretion; vagal efferent reflex; and release of tachykinins from sensory nerve endings) will be assessed at various airway sites by: (a) measuring arterio-venous differences and bronchoalveolar lavage fluid contents of histamine, leukotriene D4, prostaglandin D2, and substance P, before and during HIB in the guinea pig; (b) comparing minute ventilation vs respiratory resistance dose-response curves, before and after administration of chlorpheniramine, LY171883, (D-Arg1,D- Pro2,D-Trp7,9,Leu11) substance P, thiorphan and/or captopril, or atropine, or obtain hyperpnea dose-response curves after pretreatment with capsaicin or vagotomy; (c) relating (a) to (b); and (d) obtaining tantalum oxide bronchograms to identify changes in the sites of airway response to dry air hyperpnea, after the above interventions. These three inter-related sets of experiments in sheep and guinea pigs will provide insight into the pathophysiologic sequence by which hyperpnea leads to bronchoconstriction in guinea pigs. Clarification of the events leading to guinea pig hyperpnea-induced bronchoconstriction may suggest studies which lead to the eventual identification of the mechanisms responsible for hyperpnea-induced bronchoconstriction in asthma.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL041009-03
Application #
3358448
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1988-07-01
Project End
1993-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
3
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Chicago
Department
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
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