title: Chronic fine particulate matter exposure induces systemic vascular dysfunction via NADPH oxidase and TLR4 pathways.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  Here, we show that chronic exposure to ambient PM₂.₅ 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 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(phox) 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.
authors.affiliation: Davis Heart & Lung Research Institute, Ohio State University College of Medicine, Columbus, OH 43210, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kampfrath
authors.forename: Andrei
authors.initials: A
authors.lastname: Maiseyeu
authors.forename: Zhekang
authors.initials: Z
authors.lastname: Ying
authors.forename: Zubair
authors.initials: Z
authors.lastname: Shah
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Deiuliis
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Xu
authors.forename: Nisharahmed
authors.initials: N
authors.lastname: Kherada
authors.forename: Robert D
authors.initials: RD
authors.lastname: Brook
authors.forename: Kongara M
authors.initials: KM
authors.lastname: Reddy
authors.forename: Nitin P
authors.initials: NP
authors.lastname: Padture
authors.forename: Sampath
authors.initials: S
authors.lastname: Parthasarathy
authors.forename: Lung Chi
authors.initials: LC
authors.lastname: Chen
authors.forename: Susan
authors.initials: S
authors.lastname: Moffatt-Bruce
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Sun
authors.forename: Henning
authors.initials: H
authors.lastname: Morawietz
authors.forename: Sanjay
authors.initials: S
authors.lastname: Rajagopalan
mesh_terms: D000280:Administration, Inhalation; D000393:Air Pollutants / Q000009:adverse effects; D000818:Animals; D004781:Environmental Exposure; D004789:Enzyme Activation; D007249:Inflammation / Q000209:etiology; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019255:NADPH Oxidases / Q000378:metabolism*; D010084:Oxidation-Reduction; D010316:Particle Size; D052638:Particulate Matter / Q000008:administration & dosage / Q000009:adverse effects*; D010743:Phospholipids / Q000378:metabolism; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014652:Vascular Diseases / Q000139:chemically induced* / Q000209:etiology*
chemical_list: D000393:Air Pollutants; D052638:Particulate Matter; D010743:Phospholipids; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D019255:NADPH Oxidases