Chronic Fine Particulate Matter Exposure Induces Systemic Vascular Dysfunction via NADPH Oxidase and TLR4 Pathways

Abstract

Rationale: Chronic exposure to ambient air-borne particulate matter of 2.5) increases cardiovascular risk. The mechanisms by which inhaled ambient particles are sensed and how these effects are systemically transduced remain elusive. Objective: To investigate the molecular mechanisms by which PM_2.5 mediates inflammatory responses in a mouse model of chronic exposure. Methods and Results: Here, we show that chronic exposure to ambient PM_2.5 promotes Ly6C^high inflammatory monocyte egress from bone-marrow and mediates their entry into tissue niches where they generate reactive oxygen species via NADPH oxidase. Toll-like receptor (TLR)4 and Nox2 (gp91^phox) deficiency prevented monocyte NADPH oxidase activation in response to PM_2.5 and was associated with restoration of systemic vascular dysfunction. TLR4 activation appeared to be a prerequisite for NAPDH oxidase activation as evidenced by reduced p47^phox phosphorylation in TLR4 deficient animals. PM_2.5 exposure markedly increased oxidized phospholipid derivatives of 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (oxPAPC) in bronchioalveolar lavage fluid. Correspondingly, exposure of bone marrow–derived macrophages to oxPAPC but not PAPC recapitulated effects of chronic PM_2.5 exposure, whereas TLR4 deficiency attenuated this response. Conclusions: Taken together, our findings suggest that PM_2.5 triggers an increase in oxidized phospholipids in lungs that then mediates a systemic cellular inflammatory response through TLR4/NADPH oxidase–dependent mechanisms.