Obstructive Sleep Apnea and WTC dust: Does Chronic Intermittent Hypoxia exacerbate WTC dust induced lung injury

阻塞性睡眠呼吸暂停和世贸中心粉尘：慢性间歇性缺氧是否会加剧世贸中心粉尘引起的肺损伤

• 批准号: 10314852
• 负责人: Andrew J Gow
• 金额: $ 50万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10314852
• 关键词: Obstructive; Sleep; Apnea; WTC; dust

Project Summary Collapse of the World Trade Center (WTC) twin towers led to a large dust cloud of particles that consisted of a mixture of highly alkaline fibers that were either inhaled or swallowed and were deposited in the conducting airways of WTC responders, recovery workers and local residents. This led to both physical and chemical irritation and resulted in upper and lower airway injury resulting in chronic sinusitis, obstructive sleep apnea (OSA), bronchial wall thickening, airways obstruction and airway hyperreactivity, as well as a sarcoid like granulomatous inflammation of the lungs. Potential mechanisms of lung injury include upregulation of genes and proteins related to inflammation and oxidative stress. Additionally, metabolomic analysis suggests that oxidative stress mediates lung function decline. Since abnormal pulmonary structure and function can appear many years after the initial dust exposure, it is likely that additional oxidative stress may precipitate or worsen lung injury. Previous studies, including our own, (WTCSNORE) have shown a prevalence of 75% obstructive sleep apnea (OSA) in WTC subjects. We hypothesize that the presence of OSA in WTC responders represents a two- hit model that alters the metabolomic profile of the lung and mitochondrial function in lung macrophages resulting in exacerbated lung injury. To test this hypothesis, we will perform a longitudinal analysis of the effects of CIH following WTC dust exposure on oxidative stress markers, macrophage phenotype, mitochondrial function and physiological function of the lung in a mouse model of WTC dust exposure and identify the changing serum metabolomic profile associated with CIH. These studies will allow for the investigation of the fundamental role that macrophages play in mediating the two-hit process that results in lung injury in WTC exposed individuals. Furthermore, examination of serum biomarkers and their correlation to established processes in the animal model, will allow for the identification of novel biomarkers that can be used in future studies to track the progress of disease in WTC exposed individuals. These studies will help us achieve our long-term goal of defining the mechanisms underlying OSA worsening of the toxicity of WTC dust exposure. To test our hypothesis, in aim 1 we will analyze time related effects of CIH on WTC. In aim 2 we will perform a longitudinal analysis of the metabolomic profile in the serum and the lung of mice exposed to WTC dust and CIH. These studies have a significant clinical impact on the WTC responder population. They will provide. metabolomic profiles that will act as biomarkers of early lung injury in individuals with OSA. In addition, if OSA exacerbates lung injury, treatment of OSA may help in the prevention of WTC dust related respiratory illnesses.

项目摘要 世界贸易中心（WTC）双子塔的崩溃导致巨大的颗粒云云由一个组成 高度碱性纤维的混合物，这些纤维被吸入或吞咽，并沉积在传导中 WTC响应者，恢复工人和当地居民的航空道。这导致了物理和化学 刺激并导致上下气道损伤导致慢性鼻窦炎，阻塞性睡眠呼吸暂停 （OSA），支气管壁增厚，气道阻塞和气道高反应性，以及类似的肌酸 肺部肉芽肿性炎症。肺损伤的潜在机制包括基因上调和 与炎症和氧化应激有关的蛋白质。此外，代谢组分分析表明氧化性 压力介导肺功能下降。由于异常的肺结构和功能可以出现多年 最初的灰尘暴露后，额外的氧化应激可能会导致或恶化肺部损伤。 先前的研究，包括我们自己的（WTCSNORE），表明患病率为75％阻塞性睡眠呼吸暂停 （OSA）在WTC受试者中。我们假设WTC响应者中OSA的存在代表了两种 命中模型，以改变肺巨噬细胞中肺和线粒体功能的代谢组学谱 导致恶化的肺损伤。为了检验这一假设，我们将对 WTC粉尘暴露后CIH对氧化应激标记，巨噬细胞表型，线粒体的影响 WTC粉尘暴露的小鼠模型中肺的功能和生理功能，并确定变化 与CIH相关的血清代谢组谱。这些研究将允许调查基本 巨噬细胞在介导导致WTC暴露于肺损伤的两次打击过程中所扮演的角色 个人。此外，检查血清生物标志物及其与已建立过程的相关性 动物模型将允许识别新型生物标志物，这些生物标志物可以在以后的研究中用于跟踪 WTC暴露个人的疾病进展。这些研究将帮助我们实现我们的长期目标 定义OSA的基础机制，使WTC粉尘暴露的毒性恶化。为了检验我们的假设， 在AIM 1中，我们将分析CIH对WTC的时间相关效应。在AIM 2中，我们将对 暴露于WTC粉尘和CIH的小鼠血清和肺中的代谢组谱。这些研究有 对WTC响应者人群的重大临床影响。他们将提供。代谢组概况将采取行动 作为OSA患者早期肺损伤的生物标志物。另外，如果OSA加剧了肺损伤，则治疗 OSA可能有助于预防与WTC尘埃相关的呼吸道疾病。