Cardiovascular Toxicology

, Volume 16, Issue 2, pp 163–171 | Cite as

Inflammatory and Vasoactive Effects of Serum Following Inhalation of Varied Complex Mixtures

  • Mario J. Aragon
  • Izabela Chrobak
  • Jeremy Brower
  • Luis Roldan
  • Laura E. Fredenburgh
  • Jacob D. McDonald
  • Matthew J. CampenEmail author


Chronic cardiovascular disease is associated with air pollution exposure in epidemiology and toxicology studies. Inhaled toxicants can induce changes in serum bioactivity that impact endothelial inflammatory gene expression in vitro and impair vasorelaxation ex vivo, which are common precursors to atherosclerosis. Comparisons between single pollutants and common combustion mixtures, in terms of driving such serum inflammatory and vasoactive effects, have not been characterized. Healthy C57BL/6 mice were exposed to a single 6-h period of contrasting pollutant atmospheres: road dust, mixed vehicle emissions (MVE; a combination of gasoline and diesel engine emissions) particulate matter, mixed vehicle emissions gases, road dust plus ozone, road dust plus MVE, and hardwood smoke. Serum obtained from mice 24 h after these exposures was used as a stimulus to assess inflammatory potential in two assays: incubated with primary murine cerebrovascular endothelial cells for 4 h to measure inflammatory gene expression or applied to naïve aortic rings in an ex vivo myographic preparation. Road dust and wood smoke exposures were most potent at inducing inflammatory gene expression, while MVE atmospheres and wood smoke were most potent at impairing vasorelaxation to acetylcholine. Responses are consistent with recent reports on MVE toxicity, but reveal novel serum bioactivity related to wood smoke and road dust. These studies suggest that the compositional changes in serum and resultant bioactivity following inhalation exposure to pollutants may be highly dependent on the composition of mixtures.


Diesel Particulate matter Gasoline Exhaust Cardiovascular Wood smoke Endothelium 



This study was funded by Grants from the National Institutes of Health (R01 ES014639, R01 HL114839, HL115106, T32 HL007736) and the Environmental Protection Agency (RD-83479601-0). The views expressed in this document are solely those of the authors, and the US EPA does not endorse any products or commercial services mentioned in this publication.

Ethical standard

The authors confirm that they have no conflicts of interest, financial or otherwise, with the contents of this manuscript. Studies were conducted with full approval by the Institutional Animal Care and Use Committees of both the University of New Mexico and Lovelace Respiratory Research Institute.

Supplementary material

12012_2015_9325_MOESM1_ESM.docx (117 kb)
Supplementary material 1 (DOCX 117 kb)


  1. 1.
    Allen, R. W., Carlsten, C., Karlen, B., Leckie, S., van Eeden, S., Vedal, S., et al. (2011). An air filter intervention study of endothelial function among healthy adults in a woodsmoke-impacted community. American Journal of Respiratory and Critical Care Medicine, 183, 1222–1230.CrossRefPubMedGoogle Scholar
  2. 2.
    Bell, M. L., Ebisu, K., Leaderer, B. P., Gent, J. F., Lee, H. J., Koutrakis, P., et al. (2014). Associations of PM(2). (5) constituents and sources with hospital admissions: analysis of four counties in Connecticut and Massachusetts (USA) for persons ≥65 years of age. Environmental Health Perspectives, 122, 138–144.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Brook, R. D., Cakmak, S., Turner, M. C., Brook, J. R., Crouse, D. L., Peters, P. A., et al. (2013). Long-term fine particulate matter exposure and mortality from diabetes in Canada. Diabetes Care, 36, 3313–3320.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Campen, M., Robertson, S., Lund, A., Lucero, J., & McDonald, J. (2014). Engine exhaust particulate and gas phase contributions to vascular toxicity. Inhalation Toxicology, 26, 353–360.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Channell, M. M., Paffett, M. L., Devlin, R. B., Madden, M. C., & Campen, M. J. (2012). Circulating factors induce coronary endothelial cell activation following exposure to inhaled diesel exhaust and nitrogen dioxide in humans: evidence from a novel translational in vitro model. Toxicological Sciences, 127, 179–186.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Cung, H., Aragon, M., Anderson, J., Nawarskas, J., Roldan, C., Sood, A., Qualls, C., Campen, M. J. (2015). Characterization of a novel endothelial biosensor assay reveals increased cumulative serum inflammatory potential in stabilized coronary artery disease patients. Journal of Translational Medicine, minor revisions.Google Scholar
  7. 7.
    Forchhammer, L., Møller, P., Riddervold, I. S., Bønløkke, J., Massling, A., Sigsgaard, T., et al. (2012). Controlled human wood smoke exposure: Oxidative stress, inflammation and microvascular function. Particle and Fibre Toxicology. doi: 10.1186/1743-8977-9-7.
  8. 8.
    Hoffmann, B., Moebus, S., Dragano, N., Mohlenkamp, S., Memmesheimer, M., Erbel, R., et al. (2009). Residential traffic exposure and coronary heart disease: Results from the Heinz Nixdorf Recall Study. Biomarkers : Biochemical indicators of exposure, response, and susceptibility to chemicals, 14(Suppl 1), 74–78.CrossRefGoogle Scholar
  9. 9.
    Hunter, A. L., Unosson, J., Bosson, J. A., Langrish, J. P., Pourazar, J., Raftis, J. B., et al. (2014). Effect of wood smoke exposure on vascular function and thrombus formation in healthy fire fighters. Particle and Fibre Toxicology, 11, 62.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Liberda, E. N., Cuevas, A. K., Qu, Q., & Chen, L. C. (2014). The acute exposure effects of inhaled nickel nanoparticles on murine endothelial progenitor cells. Inhalation Toxicology, 26, 588–597.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Livak, K. J., & Schmittgen, T. D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods, 25, 402–408.CrossRefPubMedGoogle Scholar
  12. 12.
    Mauderly, J. L., & Seilkop, S. K. (2014). The National Environmental Respiratory Center (NERC) experiment in multi-pollutant air quality health research: III. Components of diesel and gasoline engine exhausts, hardwood smoke and simulated downwind coal emissions driving non-cancer biological responses in rodents. Inhalation Toxicology, 26, 668–690.CrossRefPubMedGoogle Scholar
  13. 13.
    McDonald, J. D., Barr, E. B., & White, R. K. (2004). Design, characterization, and evaluation of a small-scale diesel exhaust exposure system. Aerosol Science Technology, 38, 62–78.CrossRefGoogle Scholar
  14. 14.
    McDonald, J. D., Barr, E. B., White, R. K., Kracko, D., Chow, J. C., Zielinska, B., & Grosjean, E. (2008). Generation and characterization of gasoline engine exhaust inhalation exposure atmospheres. Inhalation Toxicology, 20, 1157–1168.CrossRefPubMedGoogle Scholar
  15. 15.
    Mercer, R. R., Scabilloni, J. F., Hubbs, A. F., Wang, L., Battelli, L. A., McKinney, W., et al. (2013). Extrapulmonary transport of MWCNT following inhalation exposure. Particle and Fibre Toxicology, 10, 38.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Mills, N. L., Tornqvist, H., Robinson, S. D., Gonzalez, M., Darnley, K., MacNee, W., et al. (2005). Diesel exhaust inhalation causes vascular dysfunction and impaired endogenous fibrinolysis. Circulation, 112, 3930–3936.CrossRefPubMedGoogle Scholar
  17. 17.
    Otterbein, L. E., Zuckerbraun, B. S., Haga, M., Liu, F., Song, R., Usheva, A., et al. (2003). Carbon monoxide suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury. Nature Medicine, 9, 183–190.CrossRefPubMedGoogle Scholar
  18. 18.
    Pope, C. A, 3rd, Burnett, R. T., Thurston, G. D., Thun, M. J., Calle, E. E., Krewski, D., & Godleski, J. J. (2004). Cardiovascular mortality and long-term exposure to particulate air pollution: epidemiological evidence of general pathophysiological pathways of disease. Circulation, 109, 71–77.CrossRefPubMedGoogle Scholar
  19. 19.
    Postlethwait, E. M., Langford, S. D., & Bidani, A. (1990). Reactive absorption of nitrogen dioxide by pulmonary epithelial lining fluid. Journal of Applied Physiology, 69, 523–531.PubMedGoogle Scholar
  20. 20.
    Postlethwait, E. M., Langford, S. D., & Bidani, A. (1994). Determinants of inhaled ozone absorption in isolated rat lungs. Toxicology and Applied Pharmacology, 125, 77–89.CrossRefPubMedGoogle Scholar
  21. 21.
    Robertson, S., Colombo, E. S., Lucas, S. N., Hall, P. R., Febbraio, M., Paffett, M. L., & Campen, M. J. (2013). CD36 mediates endothelial dysfunction downstream of circulating factors induced by O3 exposure. Toxicological Sciences, 134, 304–311.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Ross, R. (1999). Atherosclerosis—An inflammatory disease. New England Journal of Medicine, 340, 115–126.CrossRefPubMedGoogle Scholar
  23. 23.
    Sarnat, J. A., Marmur, A., Klein, M., Kim, E., Russell, A. G., Sarnat, S. E., et al. (2008). Fine particle sources and cardiorespiratory morbidity: An application of chemical mass balance and factor analytical source-apportionment methods. Environmental Health Perspectives, 116, 459–466.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Schisler, J. C., Ronnebaum, S. M., Madden, M., Channell, M. M., Campen, M. J., Willis, M. S. (2015). Endothelial inflammatory transcriptional responses to an altered plasma exposome following inhalation of diesel emissions. Inhalation Toxicology (in press).Google Scholar
  25. 25.
    Seilkop, S. K., Campen, M. J., Lund, A. K., McDonald, J. D., & Mauderly, J. L. (2012). Identification of chemical components of combustion emissions that affect pro-atherosclerotic vascular responses in mice. Inhalation Toxicology, 24, 270–287.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Unosson, J., Blomberg, A., Sandstrom, T., Muala, A., Boman, C., Nystrom, R., et al. (2013). Exposure to wood smoke increases arterial stiffness and decreases heart rate variability in humans. Particle and Fibre Toxicology, 10, 20.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Vedal, S., Campen, M. J., McDonald, J. D., Kaufman, J. D., Larson, T. V., Sampson, P. D., et al. (2013). National particle component toxicity (NPACT) initiative report on cardiovascular effects. Research Report, 178, 238.Google Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Mario J. Aragon
    • 1
  • Izabela Chrobak
    • 2
    • 3
  • Jeremy Brower
    • 3
  • Luis Roldan
    • 1
  • Laura E. Fredenburgh
    • 2
    • 3
  • Jacob D. McDonald
    • 3
  • Matthew J. Campen
    • 1
    Email author
  1. 1.College of PharmacyUniversity of New MexicoAlbuquerqueUSA
  2. 2.Brigham and Women’s HospitalBostonUSA
  3. 3.Lovelace Respiratory Research InstituteAlbuquerqueUSA

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