The overall goal of this proposal is to better understand the molecular basis for airway remodeling in children and adults with severe asthma and how it differs from mild-to-moderate asthma. In that context, we propose to study a well characterized cohort of subjects with severe asthma at baseline and two years later and contrast these findings to mild-moderate asthma, normal controls, and diseased controls (chronic bronchitis). We propose that individuals with severe asthma have more severe airway remodeling and inflammation than subjects with mild-to-moderate asthma and normal controls and that the remodeling is associated with less reversible airflow obstruction. Airway remodeling appears to develop in asthma due to a complex interaction between acute and chronic airway inflammation, insults to the airway (due to infections/toxins/environmental exposures), and underlying genetic susceptibility. Ongoing airway inflammation, epithelial desquamation/denudation (due to death or apoptosis), and repair processes, such as epithelial hyperplasia (cellular proliferation) and subepithelial fibrosis, result in abnormal structural changes in the airway. In subjects with severe asthma, this may manifest clinically as irreversible airflow obstruction and poor asthma control despite appropriate anti-inflammatory therapy. The mechanism behind this pathologic process in humans with asthma is unclear and will be better defined in this project. Furthermore, we hypothesize that a noninvasive measurement of airway wall thickness using high resolution computed tomography of the lung will correlate to the physiologic and pathologic measures of remodeling (on a segmental airway level). We will evaluate how these factors associated with remodeling are modified over time in the same individual. Accordingly, in order to better define the molecular basis for airway remodeling in severe asthma and how it differs from mild-to-moderate asthma, we propose to: (1) Define the relationship between airway remodeling and reversibility of airflow obstruction in a well characterized cohort of subjects with severe asthma; (2) Define the pro- and anti-apoptotic factors in airway epithelium associated with airway remodeling in subjects with severe asthma; and (3) Investigate whether radiologic measures of airway thickness correlate with pathologic and physiologic markers in subjects with severe asthma; and compare these findings to subjects with mild-to-moderate asthma and diseased and normal controls. The identification of the potential variables associated with remodeling and severe asthma will help identify individuals at risk who would benefit from specific targeted therapy.
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