title: Metal rich particulate matter impairs acetylcholine-mediated vasorelaxation of microvessels in mice.
abstract: BACKGROUND
  Exposure to PM2.5 (particulate matter<2.5 μm) has been associated with changes in endothelial function. PM2.5 was collected from two Chinese cities, Jinchang (JC) and Zhangye (ZH), both with similar PM2.5 concentrations. However, JC had levels of nickel (Ni), selenium (Se), copper (Cu), and arsenic (As) that were 76, 25, 17, and 7 fold higher than that measured in ZH, respectively. We used this unique PM sample to delineate the chemical components that drive pulmonary and systemic effects and explore the mechanism(s) by which vascular dysfunction is caused.
  
  
  METHODS
  Male FVB/N mice received oropharyngeal aspiration of water or PM2.5 from JC, ZH or ZH spiked with one of the following elements at the same concentrations found in the JC PM (Ni=4.76; As=2.36; Se=0.24; Cu=2.43 μg/mg) followed by evaluation of markers of pulmonary and systemic inflammation. Mesenteric arteries were isolated for gene expression or functional response to various agonists (Phenylephrine, Acetylcholine, and Sodium Nitroprusside) and inhibitors (L-NAME, Apocynin, and VAS2870) ex vivo.
  
  
  RESULTS
  Protein and total cell counts from lung lavage revealed significant pulmonary inflammation from ZH (p<0.01) and JC and ZH+NiSO4 (p<0.001) as compared to control and a significant decrease in mesenteric artery relaxation (p<0.001) and this decrease is blunted in the presence of NADPH oxidase inhibitors. Significant increases in gene expression (TNF-α, IL-6, Nos3; p<0.01; NOX4; p<0.05) were observed in JC and ZH+NiSO4, as well as significantly higher concentrations of VEGF and IL-10 (p<0.01, p<0.001; respectively).
  
  
  CONCLUSIONS
  Our results indicate that the specific toxicity observed in PM from JC is likely due to the nickel component in the PM. Further, since VAS2870 was the most successful inhibitor to return vessels to baseline relaxation values, NADPH Oxidase is implicated as the primary source of PM-induced O2•-.
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, 10987, NY, USA. amj316@nyu.edu.
authors.forename: Azita K
authors.initials: AK
authors.lastname: Cuevas
authors.affiliation: Lanzhou University School of Public Health, Lanzhou, China. niujingp@lzu.edu.cn.
authors.forename: Jingping
authors.initials: J
authors.lastname: Niu
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, 10987, NY, USA. Mianhua.Zhong@nyumc.org.
authors.forename: Mianhua
authors.initials: M
authors.lastname: Zhong
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, 10987, NY, USA. Eric.Liberda@nyu.edu.
authors.forename: Eric N
authors.initials: EN
authors.lastname: Liberda
authors.affiliation: Human Studies Division, NHEERL, USEPA, Research Triangle Park, Chapel Hill, NC, USA. Ghio.Andy@epamail.epa.
authors.forename: Andrew
authors.initials: A
authors.lastname: Ghio
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, 10987, NY, USA. Qingshan.Qu@nyumc.org.
authors.forename: Qingshan
authors.initials: Q
authors.lastname: Qu
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, 10987, NY, USA. Lung-Chi.Chen@nyumc.org.
authors.forename: Lung Chi
authors.initials: LC
authors.lastname: Chen
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001151:Arsenic / Q000737:chemistry / Q000633:toxicity; D015415:Biomarkers / Q000097:blood; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D003300:Copper / Q000737:chemistry / Q000633:toxicity; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D008815:Mice, Inbred Strains; D055806:Microvessels / Q000187:drug effects* / Q000503:physiopathology; D009532:Nickel / Q000032:analysis / Q000737:chemistry / Q000633:toxicity*; D010316:Particle Size; D052638:Particulate Matter / Q000032:analysis / Q000737:chemistry / Q000633:toxicity*; D053120:Respiratory Aspiration / Q000139:chemically induced / Q000276:immunology / Q000503:physiopathology*; D012643:Selenium / Q000737:chemistry / Q000633:toxicity; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D015415:Biomarkers; D016207:Cytokines; D052638:Particulate Matter; D003300:Copper; D009532:Nickel; D012643:Selenium; D001151:Arsenic; D000109:Acetylcholine