Distal Lung Inflammation Effect on Asthma Exacerbations

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DESCRIPTION (provided by applicant): Our limited understanding of asthma is reflected in its increasing morbidity as well as the continued presence of symptoms and spirometric decline in a subset of patients treated with maximum standard therapy. Although asthma is classically described as a large airways disease, substantial data collected over the past 3 decades underscore the importance of the distal lung in the pathophysiology of the disease. Persistent small airways inflammation, caused by daily exposure to small participate antigens and the inability of the standard formulations of inhaled corticosteroids (ICS) to reach the distal lung, may play a role in the frequency and severity of recurrent exacerbations, although prospective data is lacking. Little data is available on the role of the small airways during the acute response (early and late phase) and resolution of asthma exacerbations (AE) although there is evidence to suggest that small airways inflammation persists well beyond the time of clinical resolution of an AE. The purpose of the proposed study is to characterize the role of the small airways during the resolution of an AE induced by a cat room challenge (CRC) that results in a naturalistic exposure to Feld-1 antigen, the particle size of which is sufficiently small to penetrate the distal lung. The study will be performed in 3 phases in steroid naive, mild to moderate asthmatic subjects with documented cat allergy. Phase I will characterize the acute phase and resolution phase of the small airways to a naturalistic CRC. Phase II will evaluate whether persistent small airways inflammation, after an initial CRC, affects the acute response and resolution of a repeated asthma exacerbation, induced by a second CRC. Phase III will evaluate the impact of therapy targeted to the distal vs. proximal airways, using an extra-fine vs. a coarse ICS, on alterations in inflammation and function of small airways after a CRC. The small airways will be evaluated by the following measures: 1) novel radiographic measures of small airways air-trapping (quantitative image analysis of high resolution computed tomography performed at end-expiration), 2) classic physiologic measures of the small airways (isovolume FEF25-75%, RV, FRC, RV/TLC, closing volume), 3) impulse oscillation at different frequencies, 4) the alveolar portion of exhaled nitric oxide, and 5) immunologic biomarkers of asthma inflammation (IL-13 receptor alpha, IL-4 receptor alpha, eotaxin, RANTES, and inducible nitric oxide) assessed in bronchoscopically-obtained distal lung brushings. This study has the potential to clarify the contribution of the "silent zone" to the persistent morbidity encountered with asthma.