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 μm (PM 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.