Project 3 Heavy Metals Exacerbate Lower Respiratory Tract Infections

项目3 重金属加剧下呼吸道感染

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要经鉴定，镉、砷、锰等重金属含量较高。受影响地区的空气和土壤（拟议的超级基金地点）。重金属释放到环境对呼吸道健康有显着影响。虽然发病机制慢性阻塞性肺病（COPD）和哮喘很复杂，环境因素在这些疾病的发展过程中，接触重金属常常被忽视。降低呼吸道感染 (LRTI) 是慢性阻塞性肺病 (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。受影响地区的居民诊断出的 LRTI 比控制区居民高 30%。肺巨噬细胞在宿主防御呼吸道病原体方面发挥着关键作用。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会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由于经典激活表型的持续存在，加剧了 LRTI 和肺损伤肺巨噬细胞。这种持续性会损害损伤后肺泡上皮的修复。目标 1 的目标是确定重金属暴露小鼠的细菌或细菌是否增加。与接触媒介物的感染金黄色葡萄球菌的小鼠相比，病毒载量、肺损伤和死亡率。肺炎链球菌或呼吸道合胞病毒（RSV），由于经典激活的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巨噬细胞通过它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控制区相比，以及受影响地区居民的 BAL 液体是否损害伤口闭合并增加受损 AEC 的通透性。项目 3 的研究将定义重金属暴露增加居民 LRTI 的分子机制受影响地区和拟议的超级基金地点，提供了潜在的治疗目标，以减少这些慢性肺部疾病的恶化。