Matrix Metalloproteinase-19 as a Mediator of Airway Fibrosis in Obese Allergic Asthma

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Nearly 40% of the asthma patient population is obese. These patients exhibit increased asthma symptoms and severity. Obesity is associated with inflammatory and metabolic changes that can contribute to asthma pathobiology. Specifically, increased levels of leptin, a pro-inflammatory adipokine, and decreased secretion of glucagon-like peptide 1 (GLP-1), a peptide hormone that regulates insulin production, may augment pathogenic processes in asthma by acting directly on airway structural cells. In allergic asthma, airway epithelial cells produce pro-fibrotic mediators that activate airway fibroblasts to secrete excess extracellular matrix (ECM). These processes contribute to airway remodeling, structural changes in asthma that can result in permanent airway obstruction. The mechanisms directing airway remodeling in obese asthma are poorly understood, but in allergic asthma, these processes are directed in part by the type 2 cytokine, interleukin-13 (IL-13). Matrix metalloproteinase-19 (MMP-19) is an allergen-activated protease produced by airway epithelial cells and fibroblasts that participates in normal processing of ECM. Our preliminary data suggest that GLP-1 stimulates, while IL-13 and leptin suppress, MMP-19 production by airway cells. Our hypothesis is that obesity- and allergen-induced suppression of MMP-19 production plays an important role in the development of airway fibrosis in allergic asthma. Furthermore, GLP-1 inhibits pro-fibrotic cellular functions and halts the progression of airway fibrosis in obese, allergic humans and mice by acting to enhance airway fibroblast and epithelial cell MMP-19 secretion. To test this hypothesis, we propose two Aims. In Aim 1, we will culture primary airway epithelial cells and fibroblasts from obese and lean allergic asthmatic and obese and lean non-asthmatic subjects. We will silence MMP19 expression in these cells using CRISPR-Cas9 and determine the role of MMP-19 in pro-fibrotic cellular functions in response to leptin, IL-13 and GLP-1 or a GLP-1 receptor antagonist. In Aim 2, diet-induced obese Mmp19-I- and Mmp19+I+ mice will be concurrently challenged with house dust mite allergen for 4 weeks before undergoing vertical sleeve gastrectomy to induce GLP-1 secretion. We will assess airway fibrosis in vivo and relate these findings to GLP-1, leptin and MMP-19 levels in lung tissue, serum and bronchoalveolar lavage fluid. We will evaluate ex vivo cultured mouse lung fibroblasts for MMP-19 and ECM production. In both aims, we will relate pathologic airway changes and ex vivo cellular responses to measures of airway physiology and lung function in order to predict airway remodeling. Successful completion of these Aims will not only increase our understanding of the mechanisms directing the pathobiology of obese allergic asthma, but also will test specific interventions to treat obese asthma patients.