Drs. Permutt, Togias and colleagues have previously published evidence that patients with asthma lack a function by which lung inflation protects the airways from smooth muscle-induced obstruction. They propose that this defect is fundamental in asthma and may constitute the mechanism of airway hyperresponsiveness. The goals of this project are to better understand the role of lung inflation in asthma pathophysiology and to identify mechanism(s) which account for the lung inflation effect being poorly functional. With """"""""whole lung"""""""" and peripheral airways studies, they will demonstrate a bronchoprotective effect of lung inflation on healthy airways and will compare it to the bronchodilator one. They will further assess whether the loss of these effects is associated with greater asthma morbidity in a cross-sectional evaluation and in a therapeutic trial with inhaled glucocorticosteroids. Using high resolution computerized tomography, they will evaluate the hypotheses that patients with asthma may not be capable of stretching their airways when taking a deep breath, or that the stretch they can achieve does not benefit their airways. By comparing methacholine and allergen challenge in rhinitic-nonasthmatics in the presence and absence of deep inspirations, they will investigate the concept that the allergic reaction interferes with the beneficial effect of lung inflation. This may explain why rhinitics without asthma respond acutely to allergen inhalation similarly to asthmatics. They will first target the sulfidopeptide leukotrienes as potential mediators of such phenomenon because, in the presence of deep inspirations, these substances, when inhaled, poorly differentiate asthmatics from nonasthmatics. They will use a leukotriene antagonist to restore the effect of lung inflation after allergen challenge and will administer leukotrienes to rhinitics-nonasthmatics to mimic the allergen effect. They will also evaluate, in these subjects, whether allergen inhalation challenge has late effects on lung inflation-induced bronchoprotection. By offering an in depth understanding of the way in which airway mechanics lead to the manifestations of asthma, the project should answer many questions behind this disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL061277-01
Application #
2727420
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1998-12-15
Project End
2002-11-30
Budget Start
1998-12-15
Budget End
1999-11-30
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Pyrgos, George; Togias, Alkis; Brown, Robert H (2013) Phosphodiesterase V inhibition reduces airway responsiveness, but does not improve the beneficial effect of deep inspiration. Respiration 86:243-51
Pyrgos, George; Scichilone, Nicola; Togias, Alkis et al. (2011) Bronchodilation response to deep inspirations in asthma is dependent on airway distensibility and air trapping. J Appl Physiol 110:472-9
Skloot, Gwen S; Chandy, Dipak; Schachter, Neil et al. (2007) The bronchoprotective effect of deep inspiration is flow rate dependent. Respir Med 101:1376-82
Scichilone, Nicola; Marchese, Roberto; Soresi, Simona et al. (2007) Deep inspiration-induced changes in lung volume decrease with severity of asthma. Respir Med 101:951-6
Brown, Robert H; Pearse, David B; Pyrgos, George et al. (2006) The structural basis of airways hyperresponsiveness in asthma. J Appl Physiol 101:30-9
Scichilone, Nicola; Permutt, Solbert; Bellia, Vincenzo et al. (2005) Inhaled corticosteroids and the beneficial effect of deep inspiration in asthma. Am J Respir Crit Care Med 172:693-9
Pyrgos, George; Kapsali, Trisevgeni; Permutt, Solbert et al. (2003) Absence of deep inspiration-induced bronchoprotection against inhaled allergen. Am J Respir Crit Care Med 167:1660-3
Skloot, Gwen; Togias, Alkis (2003) Bronchodilation and bronchoprotection by deep inspiration and their relationship to bronchial hyperresponsiveness. Clin Rev Allergy Immunol 24:55-72
Peebles Jr, R S; Wagner, E M; Liu, M C et al. (2001) Allergen-induced changes in airway responsiveness are not related to indices of airway edema. J Allergy Clin Immunol 107:805-11
Scichilone, N; Pyrgos, G; Kapsali, T et al. (2001) Airways hyperresponsiveness and the effects of lung inflation. Int Arch Allergy Immunol 124:262-6

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