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

项目摘要 世界贸易中心(WTC)双子塔的倒塌导致了一大片尘埃云，其中包括 吸入或吞咽并沉积在导体中的高碱性纤维的混合物 世贸中心响应人员、恢复工作人员和当地居民的航空公司。这导致了物理和化学的双重作用。 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 阻塞性睡眠呼吸暂停综合征(OSA)、支气管壁增厚、呼吸道阻塞和气道高反应性以及结节样病变 肺部的肉芽肿性炎症。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，代谢组学分析表明，氧化 应激导致肺功能下降。由于肺结构和功能异常可出现多年 在最初的粉尘暴露后，额外的氧化应激可能会沉淀或加重肺损伤。 之前的研究，包括我们自己的，(WTCSNORE)已经表明阻塞性睡眠呼吸暂停的患病率为75% (OSA)在WTC受试者。我们假设OSA在WTC应答器中的存在代表了两个- 改变肺代谢和肺巨噬细胞线粒体功能的HIT模型 导致肺损伤加重。为了验证这一假设，我们将对 WTC粉尘接触后CIH对氧化应激标志物、巨噬细胞表型、线粒体的影响 WTC粉尘暴露小鼠肺功能和生理功能的变化 与脑出血相关的血清代谢谱。这些研究将允许调查基本的 巨噬细胞在WTC二次打击致肺损伤中的作用 个人。此外，血清生物标记物的检测及其与已建立的过程的相关性 动物模型，将允许识别新的生物标记物，这些标记物可以在未来的研究中用于追踪 WTC暴露人群的疾病进展。这些研究将帮助我们实现我们的长期目标 确定OSA导致WTC粉尘暴露毒性恶化的机制。为了检验我们的假设， 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，我们将执行纵向分析 WTC粉尘和环氧氯丙烷对小鼠血清和肺组织代谢的影响这些研究有一个 对WTC应答者群体的重大临床影响。他们会提供。代谢组谱将会起作用 作为阻塞性睡眠呼吸暂停综合征患者早期肺损伤的生物标志物。此外，如果阻塞性睡眠呼吸暂停综合征加重肺损伤，治疗 OSA的使用可能有助于预防与WTC粉尘相关的呼吸道疾病。

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.