The overall goal of this proposal is to better understand the molecular basis and structural and physiologic consequences of airway remodeling in severe asthma and how remodeling changes over time. In that context, we propose to study a well-characterized cohort of adult and pediatric subjects with severe asthma using a multidisciplinary approach that includes state-of-the-art morphometric, imaging, and physiologic measurements of airways. We will contrast these findings to those in groups with well- controlled asthma, normal controls, and diseased controls (chronic bronchitis) to identify features that can provide biologic targets unique to severe asthma. We have demonstrated that epithelial hyperplasia, goblet cell metaplasia and mucin production are features of airway remodeling in subjects with severe asthma, and that epithelial remodeling was due to increased epithelial proliferation and decreased cell death. We propose that individuals with severe asthma, in comparison to well controlled asthma, have: (I) increased airway remodeling as evidenced by goblet cell metaplasia and mucin production, (11) greater airway thickness by multidetector-row CT of the chest (MDCT) leading to ventilation defects demonstrated by hyperpolarized helium (^He) MRI and air trapping demonstrated by MDCT, and (III) airway remodeling associated with more severe and progressive airflow obstruction. We hypothesize that the goblet cell metaplasia and increased mucin we have observed in severe asthma are being driven by an IL-13- and EGFR-dependent mechanism that inhibits epithelial cell apoptosis and allows IL-13 differentiation of the airway epithelium into goblet cells (Aim I). We further hypothesize that this remodeling of segmental airways in severe asthma leads to distal ventilation defects and air trapping (Aim II). In an effort to define potential predictors of subsequent decline in lung function in severe asthma, we hypothesize that baseline airway remodeling as reflected by MDCT airway wall area (AWA%) is predictive of FEVi (post-corticosteroid/bronchodilator FEVi) decline (Aim III). The identification of potential variables associated with remodeling and severe asthma will help identify individuals at risk whom would benefit from specific targeted therapy. The concerted efforts of this project together with the SARP will lead to new insights on the mechanistic basis for severe asthma, further elucidate how it differs from mild-moderate asthma, identify potential targets for intervention, and will provide imaging metrics to objectively evaluate outcomes for new treatments.
Understanding the molecular basis of goblet cell metaplasia and mucin production in severe asthma will provide new targets for therapy. Understanding the pathophysiologic mechanism of ventilation defects and air trapping will impact therapies such as thermoplasty and provide means of evaluating new treatments noninvasively with imaging. Finally, identification of predictors of progressive accelerated lung function decline may allow for earlier intervention in at-risk patients, leading to less severe asthma subsequently.
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