Assessment of Deployment-related Particulate Matter2.5 Exposure in Immune and Pulmonary Dysfunction in Veterans

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Abstract RATIONALE: Returning Veterans deployed to Southeast Asia were exposed to high levels of airborne particulate matter below 2.5 µm (PM2.5) from burn-pit smoke and other deployment-related pollutions. Excessive PM2.5 exposure could lead to immune dysfunction, increasing susceptibility to asthma, infections, and chronic lung diseases. PM2.5 exposure associated with immune and pulmonary dysfunction in returning Veterans has not been fully elucidated. METHODS: Veterans participating in the Department of Veterans Affairs Cooperative Study (CSP #595) were randomly invited to participate in the Lung Effects of Deployment Exposure (LEDE) at four sites (Houston, Boston, Minneapolis, and Seattle). Forty-three non-smokers with and without chronic respiratory symptoms assigned to minimal or high PM2.5 exposure groups completed a standardized respiratory questionnaire and underwent a full lung function test and peripheral blood mononuclear cell (PBMC) collection. We designed a proof-of-principle study to assess immune cell responses to general stimulants ex-vivo. PBMCs (1x 106 in triplicates) were stimulated with vehicle (cell culture media), lipopolysaccharide (LPS), or T lymphocyte coactivators (anti-CD3 and -CD28 antibodies) for 24 hours to measure cytokine production. We collected supernatant and measured levels of innate and T helper (Th)1, Th2, and Th17 cytokines using LegendPlex. RESULTS: The minimally exposed participants had median FEV1=4.1L, FVC=5.0L, FEV1/FVC=0.80, TLC=6.7L, and DLCO=29 mmol/min. In those with high PM2.5 exposure, the median FEV1=3.9L, FVC=4.6L, FEV1/FVC=0.84, TLC=6.0L, and DLCO=28 mmol/min. Within the minimal PM2.5 exposure cohort, asymptomatic versus symptomatic Veterans, respectively, were median FEV1=4.4L and 2.9, FVC=5.1L and 4.9, FEV1/FVC=0.81 and 0.76, TLC=6.6 and 7.1L, and DLCO=29 and 24 mmol/min. Within the high PM2.5 exposure cohort, asymptomatic versus symptomatic Veterans, respectively, displayed median FEV1=4.3 and 3.7, FVC=5 and 4.5, FEV1/FVC=0.84 and 0.84, TLC=6.7 and 5.8, and DLCO=30 and 26. Our proof of principle ex vivo study showed LPS stimulation specifically increased proinflammatory cytokines IL-6 and TNF, while ⍺-CD3+⍺-CD28 activation increased Th2 (IL-5, IL-9, IL-22) and Th1-associated (IFN-γ, TNF) cytokines. CONCLUSION: Veterans with high PM2.5 exposure exhibited a trend for decreased FEV1, FVC, TLC, and DLCO than those minimally exposed, suggesting that high PM2.5 exposure could contribute to impaired lung function. Within the high exposure group, symptomatic Veterans displayed decreased FEV1, FVC, TLC, and DLCO, although not statistically significant except DLCO. Our ex vivo PBMC stimulation model discriminated skewed innate and adaptive cytokine signatures, enabling us to distinguish unique cytokine responses associated with increased exposure to PM2.5, decreased pulmonary function, and symptoms in returning Veterans.

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