Project 3 Heavy Metals Exacerbate Lower Respiratory Tract Infections

项目3 重金属加剧下呼吸道感染

• 批准号: 10560544
• 负责人: A BRENT CARTER
• 金额: $ 17.97万
• 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/10560544
• 关键词: Affect; Air; Area; Arsenic; Asthma; Attenuated; Bacteria; Biological Assay; Bronchitis; Cadmium; Cells; Chronic Obstructive Pulmonary Disease; Chronic lung disease; Coal; Coke; Complex; Data; Development; Dextrans; Diagnosis; Disease; Dust; Environment; Environmental Exposure; Epithelial Cells; Exposure to; Fossil Fuels; Functional disorder; Goals; Half-Life; Heavy Metals; Hospitalization; Host Defense; Human; Impairment; In Vitro; Incineration; Infection; Inflammatory; Injury; Innate Immune Response; Liquid substance; Lower Respiratory Tract Infection; Lung; Lung diseases; Macrophage; Macrophage Activation; Manganese; Mediating; Metal exposure; Mining; Molecular; Morbidity - disease rate; Municipalities; Mus; Oils; Pathogenesis; Pathologic; Permeability; Phenotype; Play; Pneumonia; Recurrence; Resolution; Respiratory syncytial virus; Role; Severities; Smoking; Soil; Source; Streptococcus pneumoniae; Testing; Tobacco; Toxic effect; Viral Load result; airway remodeling; airway repair; alveolar epithelium; asthma exacerbation; cell injury; cigarette smoke; coal-fired power plant; comparison control; fighting; genetic approach; human disease; infection burden; injured; injury and repair; lung injury; mortality; organ injury; repaired; respiratory health; respiratory pathogen; restoration; superfund site; therapeutic target; wasting; wound; wound closure

PROJECT SUMMARY / ABSTRACT The heavy metals, cadmium, arsenic, and manganese, have been identified at high levels in the air and soil of the Affected Area (proposed Superfund site). Heavy metals released into the environment have a significant effect on respiratory health. Although the pathogenesis of chronic obstructive pulmonary disease (COPD) and asthma are complex, the environmental exposure to heavy metals is often overlooked in the development of these diseases. Lower respiratory tract infections (LRTIs) are a main cause of COPD and asthma exacerbations, which contributes to the morbidity and mortality of these diseases. The residents of the Affected Area have 30% higher diagnosed LRTIs than residents from the Control Area. Lung macrophages have a critical role in host defense to respiratory pathogens. Lung macrophages not only initiate an innate immune response to infection and injury, but they are also involved in repair of injury. Alveolar epithelial cells (AEC) are injured during infection that results in lung injury by disruption of the cellular barrier. It is not known if heavy metals regulate the macrophage phenotype to hinder the repair of the AEC barrier function. We hypothesize that exposure to heavy metals exacerbates LRTI and lung injury due to the persistence of a classically activated phenotype in lung macrophages. This persistence impairs the repair of the alveolar epithelium after injury. The goals of Aim 1 are to determine if heavy metal-exposed mice have increased bacterial or viral load, lung injury, and mortality compared to vehicle-exposed mice infected with S. pneumoniae or respiratory syncytial virus (RSV) due to the persistence of classically activated lung macrophages. In Aim 2 we will utilize genetic approaches to determine the mechanism(s) by which macrophages maintain persistent classical activation. The goals of Aim 3 are to determine if macrophage phenotypic switching is impaired in residents from the Affected Area compared to the Control Area and if BAL fluid from residents in the Affected Area impairs wound closure and increases permeability of injured AEC. Studies from Project 3 will define the molecular mechanism(s) by which heavy metal exposure increases LRTIs in residents of the Affected Area and proposed Superfund site, providing a potential therapeutic target to reduce the exacerbations seen in these chronic lung diseases.

项目摘要 /摘要 重金属，镉，砷和锰已被确定 受影响区域的空气和土壤（拟议的超级基金地点）。重金属释放到 环境对呼吸健康有重大影响。虽然是 慢性阻塞性肺疾病（COPD）和哮喘很复杂，环境 这些疾病的发展通常会忽略重金属。降低 呼吸道感染（LRTIS）是COPD和哮喘加重的主要原因，这是这些原因 有助于这些疾病的发病率和死亡率。受影响地区的居民 与对照区域的居民相比，LRTI的诊断LRTI的诊断高30％。肺巨噬细胞 在对呼吸道病原体的宿主防御中起关键作用。肺巨噬细胞不仅发起 对感染和伤害的先天免疫反应，但也参与了伤害的修复。 肺泡上皮细胞（AEC）在感染期间受伤，导致肺部受伤。 细胞屏障。不知道重金属是否调节巨噬细胞表型 阻碍了AEC屏障功能的修复。我们假设暴露于重金属 由于经典激活的表型在 肺巨噬细胞。这种持久性会损害受伤后肺泡上皮的修复。 目标1的目标是确定重金属暴露的小鼠是否增加了细菌或 与感染S. 由于经典激活的持续性，肺炎或呼吸道合胞病毒（RSV） 肺巨噬细胞。在AIM 2中，我们将利用遗传方法来确定机制 巨噬细胞保持持续的经典激活。目标3的目标是 确定巨噬细胞表型转换是否在受影响区域的居民中受损 与对照区域相比，如果受影响区域的居民的BAL流体是否会损害伤口 闭合并增加受伤的AEC的渗透性。项目3的研究将定义 分子机制，重金属暴露会增加LRTI的居民的LRTI 受影响区域和拟议的超级基金站点，提供了一个潜在的治疗靶点来减少 在这些慢性肺部疾病中看到的恶化。