ACUTE-, LATE- AND RESOLUTION PHASE OF THE ASTHMATIC RESPONSE IN THE SMALL AIR

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. SPECIFIC AIMS: Primary Objective: The overall objective of this study is to characterize small airways function during the resolution of an acute exacerbation by novel radiographic techniques and physiologic measures and correlate those findings with the resolution of small airways inflammatory markers. The asthma exacerbation (AE) will be experimentally induced by a naturalistic challenge with cat antigen (Fel d I), which is known to penetrate the distal airways. Mild to moderate, steroid na¿ve asthmatic subjects will be exposed in a cat room, containing a known concentration of Fel d I per m3 of air from resident, live cats, for a sufficient period of time to provoke a 20% decline in FEV1. Distal airways response will be assessed at baseline and at various times following a cat room challenge using the following measures: 1) novel radiographic techniques (quantitative analysis of high-resolution computerized tomographic [HRCT] images of the lung acquired at residual volume) 2) physiologic studies (inspiratory capacity [IC], isovolume mid flow rate [FEF25-75%, iso], and impulse oscillation [IOS] respiratory resistance at different frequencies and IOS reactance), 3) exhaled nitric oxide (FENO), including the computed alveolar component of FENO, and 4) bioimmunologic markers (immunologic markers of distal lung inflammation obtained via bronchoscopic distal lung brushings). Once the time course to resolution of the radiographic, physiologic and inflammatory changes in the small airways is ascertained, the following secondary objectives will be addressed in future studies. Secondary Objectives: a) establish if unresolved small airways inflammation, after an initial cat room challenge, in the setting of normalized FEV1 and symptoms, predisposes to a more pronounced exacerbation after a secondary cat room challenge; b) evaluate alterations in mechanisms of small airways inflammation in individuals treated or not treated with anti-inflammatory therapy targeted to the small airways, i.e., with an extra-fine vs. a coarse inhaled corticosteroid (ICS); and c) to use the non-invasive measures of small airways abnormalities employed in this study to develop a predictive model for resolution of acute asthma exacerbations which more closely parallels the inflammatory resolution of natural acute asthma exacerbations.