Project 3 Heavy Metals Exacerbate Lower Respiratory Tract Infections

项目摘要/摘要 重金属镉、砷和锰在 受影响地区的空气和土壤(拟议的超级基金选址)。释放到环境中的重金属 环境对呼吸健康有显著影响。虽然该病的发病机制 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。更低的位置 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。受影响地区的居民 被诊断为LRTI的人比控制区的居民高30%。肺巨噬细胞 在宿主对呼吸道病原体的防御中起着关键作用。肺巨噬细胞不仅启动了 对感染和损伤的一种先天免疫反应，但它们也参与损伤的修复。 肺泡上皮细胞(AEC)在感染过程中受到损伤，感染导致肺破裂损伤。 细胞屏障。目前尚不清楚重金属是否调节巨噬细胞的表型以 阻碍AEC屏障功能的修复。我们假设暴露在重金属中 由于经典型激活的表型持续存在，导致下呼吸道感染和肺损伤加剧 肺巨噬细胞。这种持续性损害了损伤后肺泡上皮的修复。 目标1的目标是确定接触重金属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)因经典型激活而持续存在 肺巨噬细胞。在目标2中，我们将利用遗传方法来确定机制(S) 巨噬细胞通过其维持持续的经典激活。目标3的目标是 确定受影响地区的居民巨噬细胞表型转换是否受损 与对照地区相比，如果受影响地区居民的BAL液体损害伤口 闭合并增加受损血管内皮细胞的通透性。项目3中的研究将定义 重金属元素暴露增加居民下呼吸道感染的分子机制(S) 受影响地区和拟议的超级基金地点，提供潜在的治疗目标，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.