The Role of Macrophages in Deployment-related Lung Disease in OEF/OIF/OND Veterans

Roughly 3 million U.S. military personnel were deployed to support operations in Southwest Asia and Afghanistan since 2001. The vast majority experienced deployment-related respiratory exposures (DRREs) from a combination of burn pit combustion products, particulate matter, and chemical toxins, and many have developed respiratory symptoms that are now service-connected. Deployment-related lung disease (DRLD) has symptoms that overlap with bronchiolitis and asthma, but the pathobiology remains unclear and controversial. There is a significant need to develop diagnostic criteria and therapy for long-term military readiness. Pulmonary macrophages (pMacs) are the sentinels of the lung and are the first immune cells to encounter inhaled toxins. In mouse models, we have shown that aerosolized deployment-related toxins result in three key alterations to pMacs: (1) sustained intracellular accumulation of toxins, (2) durable epigenetic alterations to inflammatory pathways, and (3) phagocytic and tissue repair dysfunction. Notably, we also found accumulation of activated pMacs in lung tissue from deployed OEF/OIF/OND Veterans. We hypothesize that DRREs induce epigenetic alterations to homeostatic pathways in pMacs resulting in long-term dysfunction and chronic lung disease. Our proposed studies aim to understand which DRREs contribute most to pMac dysfunction, how pMacs contribute to DRLD, move closer to diagnostic criteria, and test a targeted therapy. To achieve these goals, we will first define the specific functional and genomic changes that occur to macrophages based on the DRRE (e.g., jet fuel vs. sand vs. pesticides). We will conduct paired RNA-seq with ATAC-seq and DNA methylation analysis to identify sustained epigenetic adaptations which regulate gene expression. Next, we will use our established mouse model of DRREs with adoptive transfer and selective depletion of pMacs to define their role in the development of pulmonary pathology and dysfunction. Finally, we will evaluate the ability to repurpose a novel immune-targeted drug to prevent and/or revert exposure-induced immunopathology in our DRRE mouse models. Collectively, these studies directly address several programmatic goals related to DRREs: (1) understand pathobiology, (2) evaluate immune parameters, and (3) define epigenetic signatures. Our proposal is innovative because it focuses on epigenetic changes to immune cells that can be detected in sputum and we will test a targeted drug that is already available. This could have high impact for Veterans and active U.S. military as the pathobiology and diagnostic criteria for DRLD remain a challenge for clinicians and no targeted therapeutic options are available.