Abstract 21645: Chronic Fine Particulate Matter Exposure Mobilizes CD11b+Ly6C+ Monocytes and Induces Vascular Dysfunction via TLR4 Pathways
Background: Chronic exposure to ambient air particulate matter <2.5 μm (PM2.5) increases the risk of cardiovascular events. The mechanisms by which inhaled particles are sensed, and how these effects are systemically transduced remain elusive.
Methods: Male TLR4wt TLR4d, NOX2wt and NOX2−/− mice (n=12/group) and mice expressing YFP under control of a monocyte specific c-fms promoter (c-fmsYFP) were exposed to filtered air (FA) or concentrated PM2.5 for 20 weeks. Lung inflammatory response and levels of oxidized phospholipid derivatives of 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (oxPAPC) in bronchioalveolar lavage fluid (BALF) were assessed by liquid chromatography-mass spectrometry. Monocyte subsets were evaluated by flow cytometry. Microvascular and macrovascular function were assessed by intravital microscopy and myography.
Results: Chronic PM2.5 exposure increased Ly6Chigh inflammatory monocytes in the blood (TLR4wt FA 15±3% vs. TLR4d PM2.5 25±5%), promoted egress from bone-marrow and mediated entry into microvascular and perivascular depots where they generated superoxide (1.5 fold increase vs. TLR4wt FA) via a TLR4/IRAK dependent phosphorylation of p47 subunit of NADPH oxidase. TLR4 deficiency prevented monocyte egress from bone marrow reservoirs to tissue niches including perivascular fat and restored systemic vascular dysfunction. The mechanism for PM2.5 mediated tissue infiltration involved up-regulation of CCR2 on monocytes in conjunction with elevated CCL2 in plasma (1.5 fold increase vs TLR4wt FA) and in target tissues such as the lung (4 fold increase vs TLR4wt FA). PM2.5 exposure markedly increased oxPAPC content in BALF of TLR4wt animals as compared to TLR4wt FA. Correspondingly, exposure of primary bone marrow derived monocytes to oxPAPC but not PAPC, recapitulated effects of chronic PM2.5 exposure.
Conclusions: Our findings suggest that chronic PM2.5 exposure triggers an increase in oxidized phospholipids in the lung that may mediate systemic activation of monocytes through TLR4 and NADPH oxidase dependent mechanisms.
- © 2010 by American Heart Association, Inc.