Project 2Asthma in Children Exposed to Heavy Metals

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SUMMARY Environmental exposure of the lung to airborne particulate matter (PM) containing mixed heavy metals contributes to development of chronic lung diseases, including asthma. These diseases are classically associated with dysregulated epithelial-mesenchymal communication. PM with a particulate size of ≤2.5 µm (PM2.5) contain high levels of heavy metals, including cadmium (Cd), arsenic (As), and manganese (Mn). However, the mechanisms of how these heavy metals contribute to disease pathogenesis are unknown. In support of this project, we detected elevated levels of heavy metals in the serum/urine of residents from the Environmental Protection Agency (EPA) designated National Priorities List (NPL) Superfund site in North Birmingham. Asthmatic children from this Affected Area have evidence of systemic heavy metals exposure, as evidenced by higher urinary levels of arsenic. Bronchoalveolar lavage (BAL) fluid obtained by bronchoscopy of asthmatic individuals from this Affected Area contain epithelial cell-derived exosomes that package mitochondria. Additionally, BAL-derived exosomes from human asthmatic subjects are skewed towards a higher concentration of anti-apoptotic sphingolipids (sphingosine-1-phoshate > ceramide) by SWATH- lipidomics analysis. These exosomes are fibrogenic as they induce reprogramming of fibroblasts to an apoptosis-resistant and fibrogenic phenotype. Animal studies demonstrate that intra-tracheal instillation of heavy metals induces peribronchial fibrosis in mice, providing an opportunity to generate proof-of-concept pre- clinical data in support of targeting pro-inflammatory and pro-fibrotic sphingolipid pathways in environmental asthma. The hypothesis to be tested in this project is that heavy metal exposures in children induce airway epithelium injury/activation that triggers the release of exosomal lipids to activate fibroblasts/smooth muscle cells that contribute to airway hyper-responsiveness and remodeling in asthma. The specific aims are to: (1) determine the mechanisms of heavy metal-induced exosomal lipid signaling that activates sub-epithelial mesenchymal cells (SMCs/Fbs); (2) determine the role of lipid mediators/exosomes released by bronchial epithelial cells in airway hyper-responsiveness and remodeling in mice exposed to heavy metals; and (3) determine whether heavy metal exposures are associated with asthma severity and increased levels of plasma, EBC and sputum lipid biomarkers in children residing in the North Birmingham NPL Superfund site. These studies will provide new insights into the impact of heavy metal exposure on asthma susceptibility and severity; on novel mechanisms of epithelial-mesenchymal communication by fibrogenic exosomes; and development of new therapeutic approaches to the treatment of chronic asthma associated with heavy metal exposures.