Project 3 Heavy Metals Exacerbate Lower Respiratory Tract Infections

项目总结/摘要 重金属，镉，砷和锰，已被确定在高水平， 受影响地区（拟议超级基金地点）的空气和土壤。重金属释放到 环境对呼吸系统健康有很大的影响。虽然发病机制 慢性阻塞性肺疾病（COPD）和哮喘是复杂的，环境 在这些疾病的发展过程中，接触重金属往往被忽视。低 呼吸道感染（LRTI）是COPD和哮喘恶化的主要原因， 导致这些疾病的发病率和死亡率。受灾地区居民 比控制区的居民高出30%。肺巨噬细胞 在宿主防御呼吸道病原体方面起着关键作用。肺巨噬细胞不仅启动 对感染和损伤的先天免疫反应，但它们也参与损伤的修复。 肺泡上皮细胞（AEC）在感染过程中受损，导致肺损伤， 的细胞屏障。目前尚不清楚重金属是否调节巨噬细胞表型， 阻碍AEC屏障功能的修复。我们假设接触重金属 加重LRTI和肺损伤，这是由于在LRTI中经典活化表型的持续存在。 肺巨噬细胞这种持续性损害损伤后肺泡上皮的修复。 目的1的目标是确定重金属暴露的小鼠是否增加了细菌或 病毒载量、肺损伤和死亡率与感染S. 肺炎或呼吸道合胞病毒（RSV），由于经典活化的 肺巨噬细胞在目标2中，我们将利用遗传学方法来确定机制 巨噬细胞通过其维持持续的经典激活。目标3的目标是 确定受影响地区居民的巨噬细胞表型转换是否受损 与对照区相比，如果受影响区居民的BAL液损害伤口， 关闭并增加受损AEC的渗透性。项目3的研究将定义 重金属暴露增加当地居民LRTI的分子机制 受影响地区和拟议的超级基金地点，提供了一个潜在的治疗目标，以减少 这些慢性肺部疾病的恶化。

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.