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Introduction and Hypothesis:Fine particulate matter ? 2.5 mm (PM2.5) air pollution poses a pervasive environmental health threat that contributes to cardiovascular disease (CVD). We previously demonstrated that PM2.5 links to CVD via a mechanism that involves heightened arterial inflammation. Herein we hypothesize that PM2.5 exposure increases leukopoietic activity (in the bone marrow (BM) and spleen) and that this leukopoietic activity mediates the association between PM2.5 exposure and arterial inflammation.Methods:Individuals (N=503, median age (IQR): 55 (44-66) years, 42% male) without known CVD or active malignancy underwent clinical 18F-FDG-PET/CT imaging (2005-2008). Using validated PET/CT methods, leukopoietic (BM and spleen) activities and arterial inflammation were measured (as target-to-background-ratios [TBR]). Average annual PM2.5 exposures were modeled using the United States Environment Protection Agency Air Quality Index based on each individual?s home address. Linear regression and mediation analysis were used.Results:Annual average PM2.5 exposure associates with BM activity (standardized ? [95% CI]: 0.129 [0.042, 0.215], P=0.004) and spleen activity (0.110 [0.021, 0.199], P=0.015) in fully- adjusted* models. Higher pollution (< vs. ? median value) associated with higher BM activity (P=0.008 Fig. 1A) and spleen activity (P=0.006 Fig. 1B). Moreover, mediation analysis demonstrated that the path of: PM2.5 exposure -> leukopoietic tissue activity -> arterial inflammation is significant (? [95% CI] = 0.077 [0.0255, 0.1361], P<0.05).Conclusions:High PM2.5 exposure associates with heightened leukopoietic tissue activity. This heightened leukopoietic activity mediates the link between air pollution and arterial inflammation. These findings suggest a biological mechanism by which increased PM2.5 exposure potentiates CVD.