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

• Published in: Circulation research Vol. 108; no. 6; pp. 716 - 726
• Main Authors: Kampfrath, Thomas, Maiseyeu, Andrei, Ying, Zhekang, Shah, Zubair, Deiuliis, Jeffrey A, Xu, Xiaohua, Kherada, Nisharahmed, Brook, Robert D, Reddy, Kongara M, Padture, Nitin P, Parthasarathy, Sampath, Chen, Lung Chi, Moffatt-Bruce, Susan, Sun, Qinghua, Morawietz, Henning, Rajagopalan, Sanjay
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 18.03.2011; Lippincott Williams & Wilkins
• Subjects: Administration, Inhalation; Air Pollutants - adverse effects; Animals; Biological and medical sciences; Environmental Exposure; Enzyme Activation; Fundamental and applied biological sciences. Psychology; Inflammation - etiology; Lung - metabolism; Male; Mice; Mice, Inbred Strains; Mice, Knockout; Mice, Transgenic; NADPH Oxidases - metabolism; Oxidation-Reduction; Particle Size; Particulate Matter - administration & dosage; Particulate Matter - adverse effects; Phospholipids - metabolism; Time Factors; Toll-Like Receptor 4 - metabolism; Vascular Diseases - chemically induced; Vascular Diseases - etiology; Vertebrates: cardiovascular system; NADPH; Monocyte; Enzyme; Oxidase; Toll-like receptor 4; Phospholipid; Toll like receptor; particulate matter; Vertebrata; Chronic; Mammalia; Dysfunction; oxidized phospholipids; Oxidoreductases; Circulatory system; superoxide
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.110.237560

RATIONALE:Chronic exposure to ambient air-borne particulate matter of <2.5 μm (PM2.5) 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 PM2.5 mediates inflammatory responses in a mouse model of chronic exposure. METHODS AND RESULTS:Here, we show that chronic exposure to ambient PM2.5 promotes Ly6C 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) deficiency prevented monocyte NADPH oxidase activation in response to PM2.5 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 phosphorylation in TLR4 deficient animals. PM2.5 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 PM2.5 exposure, whereas TLR4 deficiency attenuated this response. CONCLUSIONS:Taken together, our findings suggest that PM2.5 triggers an increase in oxidized phospholipids in lungs that then mediates a systemic cellular inflammatory response through TLR4/NADPH oxidase–dependent mechanisms.