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

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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.