Project 2Asthma in Children Exposed to Heavy Metals

项目 2 接触重金属的儿童患哮喘

• 批准号: 10337088
• 负责人: Jessy Satyadas Deshane
• 金额: $ 18.07万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10337088
• 关键词: Affect; Airborne Particulate Matter; Animals; Apoptosis; Apoptotic; Area; Arsenic; Asthma; Biological Markers; Blood; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Bronchoscopy; Cadmium; Cell Communication; Cell Proliferation; Cells; Cellular Stress; Ceramides; Child; Childhood Asthma; Chronic; Chronic Obstructive Pulmonary Disease; Chronic lung disease; Clinical Data; Code; Communication; Development; Disease; Environment; Environmental Exposure; Epidemiology; Epithelial; Epithelial Cells; Equilibrium; Experimental Models; Exposure to; Fibroblasts; Fibrosis; Heavy Metals; Human; In Vitro; Incidence; Individual; Inflammatory; Inflammatory Response; Lipids; Location; Lung; Lung diseases; Manganese; Mesenchymal; Metal exposure; Mitochondria; Modeling; Mus; Particulate; Particulate Matter; Pathogenesis; Pathway interactions; Phenotype; Plasma; Population; Preclinical Testing; Predisposition; Reporting; Resistance; Role; Serum; Severities; Signal Transduction; Smooth Muscle Myocytes; Sphingolipids; Sphingosine; Sputum; T-Lymphocyte; Testing; United States Environmental Protection Agency; Urine; airway epithelium; airway hyperresponsiveness; airway remodeling; asthmatic; asthmatic airway; bronchial epithelium; demographics; epithelial injury; exosome; extracellular vesicles; fine particles; insight; lipid mediator; lipid metabolism; lipidomics; mitochondrial dysfunction; novel; novel therapeutic intervention; pre-clinical; preclinical efficacy; response; superfund site; urinary

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.

总结 肺对含混合重金属的空气颗粒物（PM）的环境暴露 导致包括哮喘在内的慢性肺部疾病的发展。这些疾病是典型的 与上皮间质通讯失调有关。颗粒尺寸≤2.5 µm的PM （PM2.5）含有高水平的重金属，包括镉（Cd）、砷（As）和锰（Mn）。 然而，这些重金属如何有助于疾病的发病机制是未知的。在 为支持这项计划，我们检测到来自 环境保护署（EPA）指定的国家优先事项清单（NPL）超级基金网站在北 伯明翰来自该受影响地区的哮喘儿童有全身重金属暴露的证据， 尿中砷的含量更高通过支气管镜检查获得支气管肺泡灌洗液（BAL）， 来自该受影响地区的哮喘个体含有上皮细胞来源的外泌体， 线粒体此外，来自人哮喘受试者的BAL来源的外泌体偏向于哮喘患者。 通过SWATH的较高浓度的抗凋亡鞘脂（鞘氨醇-1-磷酸盐>神经酰胺）- 脂质组学分析。这些外泌体是纤维化的，因为它们诱导成纤维细胞重编程成纤维细胞。 抗骨化和纤维化表型。动物研究表明，气管内滴注 重金属诱导小鼠支气管周围纤维化，提供了一个机会，以产生概念验证前， 支持靶向环境中促炎和促纤维化鞘脂途径的临床数据 哮喘 本项目中要检验的假设是儿童重金属暴露会导致气道 上皮损伤/激活，触发外泌体脂质释放以激活成纤维细胞/平滑肌 这些细胞导致哮喘中的气道高反应性和重塑。具体目标是：（1） 确定重金属诱导的外泌体脂质信号转导激活上皮下细胞的机制， 间充质细胞（SMC/Fbs）;（2）确定支气管炎释放的脂质介质/外泌体的作用 重金属暴露小鼠气道高反应性和重塑中的上皮细胞;和（3） 确定重金属暴露是否与哮喘的严重程度和 血浆、EBC和痰液脂质生物标志物在居住在北伯明翰NPL超级基金网站的儿童。 这些研究将为重金属暴露对哮喘易感性的影响提供新的见解 和严重程度;通过纤维化外泌体进行上皮-间充质通讯的新机制;以及 开发新的治疗方法来治疗与重金属相关的慢性哮喘 暴露。