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: 10459204
• 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/10459204
• 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）双子塔的倒塌导致了一个巨大的尘埃云， 被吸入或吞下并沉积在导管中的高碱性纤维混合物 WTC应急人员、救援人员和当地居民的航空公司。这导致了物理和化学 刺激并导致上、下呼吸道损伤，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，以及类肉瘤 肺部的肉芽肿性炎症。肺损伤的潜在机制包括基因的上调， 与炎症和氧化应激相关的蛋白质。此外，代谢组学分析表明， 应激介导肺功能下降。由于肺结构和功能的异常可以出现多年 在最初的粉尘暴露之后，额外的氧化应激可能会加速或加重肺损伤。 以前的研究，包括我们自己的研究，（WTCSNORE）已经显示75%的阻塞性睡眠呼吸暂停的患病率 (OSA)在WTC主题中。我们假设在WTC应答者中存在OSA代表了两个- 改变肺代谢组学特征和肺巨噬细胞线粒体功能的命中模型 导致肺损伤加重。为了验证这一假设，我们将对 CIH对氧化应激标志物、巨噬细胞表型、线粒体 肺功能和生理功能的变化，并确定其变化的机制。 与CIH相关的血清代谢组学特征。这些研究将允许调查的基本 巨噬细胞在介导导致WTC暴露肺损伤的两次打击过程中的作用 个体此外，血清生物标志物的检查及其与免疫学中已建立的过程的相关性， 动物模型，将允许识别新的生物标志物，可用于未来的研究，以跟踪 WTC暴露个体的疾病进展。这些研究将帮助我们实现我们的长期目标， 明确了OSA加重世贸中心粉尘暴露毒性的机制。为了验证我们的假设， 在目标1中，我们将分析CIH对WTC的时间相关效应。在目标2中，我们将对以下方面进行纵向分析： 暴露于WTC粉尘和CIH的小鼠的血清和肺中的代谢组学谱。这些研究有 对WTC应答人群有显著临床影响。他们会提供。代谢组学特征， 作为OSA患者早期肺损伤的生物标志物。此外，如果OSA加重肺损伤，治疗 OSA可能有助于预防与世贸中心灰尘有关的呼吸道疾病。