Airway Inflammation and Airway Remodeling in Severe Asthma

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Airway remodeling is the term applied to the structural changes observed in the airway in asthma, and includes an increase in airway wall thickness which is associated with an increase in airway smooth muscle (ASM) mass, sub-epithelial fibrosis, mucus metaplasia of epithelial cells, abnormalities in composition of the extracellular matrix, and an increase in peribronchial vascularity. Although current NIH guidelines recommend maintaining a goal of normal lung function in asthma, current therapeutic strategies in asthma are not able to specifically target airway remodeling as the cellular and molecular mechanisms that result in remodeling are not well defined. Studies have also demonstrated that severe asthmatics with increased ASM on endobronchial biopsy have lower lung function (FEV1) compared to asthmatics with less ASM. Thus, ASM remodeling may contribute significantly to lower FEV1 in severe asthma. Although severe asthmatics comprise only approximately 5% of all asthmatics, they utilize a significant amount of health care resources (approximately 40% of the estimated $50 billion direct costs of asthma/year in the USA). As airway remodeling in severe asthma can contribute to lower lung function and a greater decline in lung function, there is an important need to identify mechanisms by which airway remodeling is mediated so that potential novel therapies could be directed at these pathways. The UCSD AADCRC will test the hypothesis that novel non- TH2-based inflammatory pathways in immune cells, inflammatory cells and epithelial cells mediate airway remodeling in severe asthma. In support of this overall hypothesis, Project 1 (Broide) has identified that Gasdermin A (GSDMA) is expressed at increased levels in epithelial cells in asthma, inhibits antiviral defense pathways in epithelium, which can trigger severe RV-induced asthma exacerbations with decline in lung function and airway remodeling. Project 2 (Croft) has identified that TNF family members LIGHT and TL1A (both increased expression in severe asthma) can directly induce human ASM and fibroblast remodeling underscoring the importance of this pathway to remodeling in severe asthma. Project 3 (Vijayanand) has identified increased frequency of a novel T cell population (i.e. cytotoxic TRM cells) in the airways of severe asthmatics, which may help to explain persistent T cell-driven inflammation and airway remodeling not due to known T cell populations (TH2 or TH1). We anticipate that each of the thee projects will identify selective pathways to airway remodeling, as well as shared pathways to remodeling that we have identified related to TRM cells, LIGHT/TL1A, and GSDMA. Novel pathways inducing airway remodeling in severe asthma will be tested in each project using human airway structural cells and TRM cells obtained by BAL, brushing, and endobronchial biopsy by “Severe Asthma Clinical Core B” from severe asthmatics and controls (mild asthma; non-asthma). Overall, these studies will identify potential novel therapeutic targets to inhibit airway remodeling and prevent decline in lung function in severe asthma.