ABSTRACT~Obesity, a major comorbidity and a potential modulator of asthma, affects nearly 40% of asthmatics in the U.S., and increases its severity. Obese asthmatics do not respond as well to conventional anti-inflammatory therapies and new biologics targeting asthma are less effective in obese asthmatics compared to lean. Very little research has been conducted in obese animals or obese asthmatics, resulting in a major knowledge deficit.~A key feature of asthma is airway remodeling and fibrosis, broadly defined as a change in distribution, thickness, composition, mass or volume of structural components of the airway wall of patients relative to healthy patients. Airway remodeling is difficult to diagnose in obese patients as mechanical changes in chest wall compliance can contribute to the physiological changes seen. Classically, evidence of airway remodeling and fibrosis are revealed as fixed airway obstruction on spirometry. However, spirometry is not only insensitive to the peripheral airways, where airway remodeling occurs, but is fundamentally incapable of localizing the sites of remodeling and fibrosis. Thus, a critical research limitation in the study of airway remodeling and fibrosis in asthma is defining regions of disease activity to explore disease-specific mechanisms. To understand the nature of airway remodeling and fibrosis in obese asthma and to rapidly screen for novel therapies requires translation between preclinical models and patients, while using advanced imaging. Recent work in asthma using 3D functional imaging with 129Xe MRI has revealed the location of both reversible and fixed ventilation defects (defined based on bronchodilator responsivity). Several studies suggest that fixed defects represent sites of airway remodeling and fibrosis, but to date, this has been inferred indirectly from sputum analyses and CT scans. The central hypothesis is that sites of abnormal ventilation on 129XeMRI represent areas of airway remodeling and fibrosis and are enriched with fibroblasts that are invasive, proliferative and fibrogenic. It is further hypothesized that regional alterations in oxidant stress driving the production of transforming growth factor-beta (TGF-β) direct pro-remodeling fibroblast functions. Lastly, it is hypothesized that 129XeMRI will be a sensitive and specific biomarker of airway remodeling and fibrosis in obese asthmatics and rat models of obese asthma. By leveraging our excellence in clinical asthma, bronchoscopy, and translational expertise in cell function/signaling and 3D MR imaging in both patients and animal models, both ex vivo cell-specific mechanistic studies and in vivo animal model studies will be conducted to uncover the mechanisms of molecular and cellular function through the following Specific Aims: Aim 1) Identify the pathology, structural cell profile (airway fibroblast and epithelial cell) and redox status corresponding to regional areas of fixed and reversible post-bronchodilator defects (BD) in obese asthmatics; 2) Define the cellular requirement for redox-mediated TGF-β signaling between airway epithelial cells and fibroblasts driving regional remodeling in obese asthma; 3) Develop non-invasive 3D imaging techniques to assess airway regional remodeling in experimental rodent models of obese asthma.
40% of all asthma patients in the US are obese. Obese asthmatics have more severe disease than lean asthmatics and do not respond as well to conventional anti-inflammatory therapies. This proposal will utilize 3D functional imaging with 129XeMRI and single cell RNA sequencing to study mechanisms driving regional airway remodeling and fibrosis in obese asthma subjects and in preclinical models of obese asthma.