Since 2001, over 3 million United States military personnel and contractors have been deployed to Southwest Asia and Afghanistan where they have been exposed to airborne particulate matter (PM) arising from a combination of sandstorms, explosive blasts and combat-related dust contaminated with toxic pollutants from local industries, burn pit combustion products, and diesel exhaust. An unknown number of military personnel have returned from deployment with persistent respiratory symptoms that limit their ability to meet physical fitness requirements of active duty service and contribute to long term disability. This application will examine the role of immune cells of the respiratory system in causing deployment related lung disease. We will use existing (banked) biological samples obtained from military personnel previously deployed to Southwest Asia who have ongoing respiratory symptoms after deployment. We will analyze the samples using sophisticated molecular (single cell RNA analysis) and protein level (CyTOF mass cytometry) technique to characterize specific populations of immune cells in the lung and how these differ between previously deployed military personnel and healthy subjects. Once we learn the cellular signaling pathways that are linked to these alterations, we will experimentally test their importance in a culture system being thin slices of human lung obtained from organ donor's unused for transplant. In the system, we can test the effects of drugs and also gene therapies to try and prevent the damage to the lung. The ultimate goal of this proposal is to identify novel therapeutic targets in order to diminish injury to the lung and the long-term respiratory consequences of deployment-related lung disease.