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.

概括 肺部的环境暴露于含有混合重金属的空气传播特定物质（PM） 有助于包括哮喘在内的慢性肺部疾病的发展。这些疾病是经典的 与上皮 - 间质通信失调有关。特定尺寸≤2.5µm的PM （PM2.5）含有高水平的重金属，包括镉（CD），砷（AS）和锰（MN）。 但是，这些重金属如何促进疾病发病机理的机制尚不清楚。 支持该项目，我们检测到居民的血清/尿液中的重金属水平升高 环境保护局（EPA）指定国家优先级列表（NPL）超级基金网站 伯明翰。来自该受影响地区的哮喘儿童具有全身性重金属暴露的证据，因为 砷的尿液水平较高。通过支气管镜通过支气管镜检查的支气管肺泡灌洗 来自该受影响区域的哮喘患者包含包装的上皮细胞衍生的外泌体 线粒体。此外，来自人类哮喘受试者的Bal衍生的外泌体偏向于 较高浓度的抗凋亡鞘脂（鞘氨酸-1-磷酸盐>神经酰胺） 脂质组学分析。这些外泌体是纤维纤维的，因为它们诱导成纤维细胞重编程为 抗细胞凋亡和纤维化表型。动物研究表明，气体内滴注 重金属在小鼠中诱导周环纤维化，为产生概念证明的机会 支持靶向促炎和促纤维化鞘脂途径的临床数据 哮喘。 该项目要检验的假设是，重金属暴露在儿童中影响气道 上皮损伤/激活触发外泌体脂质的释放以激活成纤维细胞/平滑肌 在哮喘中导致气道高反应性和重塑的细胞。具体目的是：（1） 确定重金属诱导的外泌体脂质信号的机制，该信号激活下皮 间充质细胞（SMC/FBS）； （2）确定支气管释放的脂质介质/外泌体的作用 暴露于重金属的小鼠中气道高反应性和重塑的上皮细胞； （3） 确定重金属暴露是否与哮喘的严重程度和水平增加有关 居住在北伯明翰NPL Superfund网站的儿童中的血浆，EBC和痰脂质生物标志物。 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 和严重性；关于纤维外泌体上皮 - 间质通信的新机制；和 开发新的治疗方法来治疗与重金属相关的慢性哮喘 暴露。