2011 Progress Report: Novel Markers of Air Pollution-induced Vascular Toxicity

EPA Grant Number: R833990
Title: Novel Markers of Air Pollution-induced Vascular Toxicity
Investigators: Campen, Matthew J. , Lund, Amie K.
Institution: University of New Mexico
EPA Project Officer: Nolt-Helms, Cynthia
Project Period: November 1, 2008 through October 31, 2011 (Extended to October 31, 2012)
Project Period Covered by this Report: November 1, 2010 through October 31,2011
Project Amount: $500,000
RFA: Development of Environmental Health Outcome Indicators (2007) RFA Text |  Recipients Lists
Research Category: Health Effects , Health

Objective:

Efforts to reduce the burden of heart disease and stroke have been hampered by a lack of knowledge in key areas including, but not limited to, environmental factors that may predispose susceptible individuals to plaque rupture as well as detrimental pathological effects associated with already increased levels of factors in the circulation or tissue. The objective of the present project is to characterize the role of known factors associated with progression of atherosclerosis associated with exposure to ubiquitous environmental air pollutants, such as diesel and gasoline engine exhaust. Furthermore, we have examined the role of oxidized low density lipoprotein (oxLDL) acting through the LOX-1 receptor as a mediator of the induction of vascular proteinases associated with plaque instability.

Because we have seen very clearly two predominant outcomes in our toxicological assays (vascular lipid peroxidation and inflammation), we wished to examine: (1) whether specific receptors, such as LOX-1, might link these outcomes; and (2) whether other biomarkers might arise from within these pathways that may represent more robust indicators of exposure.

Progress Summary:

In Specific Aim 1, we proposed to assay hypothesized markers in plasma and aortic tissue from mice exposed to various pollutant atmospheres. These studies will link the plasma markers with their mechanistic origins.

  • Mouse plasma from 7- and 50-day exposures to diesel emissions, coal combustion, and woodsmoke combustion have been transferred from LRRI to UNM for analysis. We have completed most proposed assays on the 50-day samples. Interestingly, the responses of LOX-1 are quite different compared to what we have seen acutely, with a significant downregulation in the diesel exposed mice. OPN showed minimal changes, possibly a reduction in the medium concentration of diesel. We are nearly finished with analyzing the 7-day samples and also investigating related markers. 
  • In Specific Aim 2, we proposed to test the role of LOX-1 scavenger receptors in mediating the vascular effects of inhaled pollutants. We hypothesized that oxidatively modified phospholipids may be a link between the lung and systemic circulation; scavenger receptors are the likely mediating intermediary. We have completed Aim 2, treating mice with an antibody to LOX-1, to selectively block the function of this pathway during exposures. As predicted, we observed a complete blockade of the systemic vascular lipid peroxidation caused by exposure to vehicular emissions (in this case, a combination of diesel and gasoline emissions; Figure 1). Similarly, reductions in intravascular accumulation of macrophages, along with mRNA induction of a number of markers, were observed due to the LOX-1 blockade. Thus, Aim 2 confirms the importance of the LOX-1 pathway in driving the systemic vascular effects of inhaled emissions.

 

 
  • In Specific Aim 3, we proposed to use the information obtained in Specific Aims 1 and 2 to develop hypotheses for protein or biochemical markers to test in human plasma. We have confirmed that relative levels of soluble LOX-1 in the plasma of human subjects become elevated following controlled exposure to diesel exhaust. We are currently analyzing similar samples from humans exposed to a number of related pollutants, including nitrogen dioxide, particulate matter, and ozone. 
  • We also expanded this aim to consider characterization of circulating LOX-1 and oxLDL in human clinical and community populations. Although controlled exposures were of interest from the outset, our success in observing alterations in these circulating biomarkers led us to consider if these would have value in clinical or community populations, where all samples are collected in a cross-sectional design. We have found that LOX-1 simply has too much inter-individual variability for which we cannot predict. The value of LOX-1 for cross-sectional study designs is therefore likely to be highly limited. However, oxLDL has been found to be upregulated in association with levels of arsenic in drinking water (Harmon et al., 2011,2012). Also, in a clinical population of women considered healthy, asthmatic, obese, or obese and asthmatic, oxLDL was found to be significantly elevated in the obese and asthmatic group (data as yet unpublished). 
  • The most substantial finding to arise from this Aim was that plasma from humans exposed to nitrogen dioxide (500 ppb for 2 hours) or diesel exhaust (100 μg/m3 for 2 hours) could induce endothelial activation, as measured by the expression of vascular cell adhesion molecule (VCAM-1) and intracellular adhesion molecule (ICAM-1) mRNA. This assay, developed around ideas in the original grant, advances the research project in an entirely novel, translational, and informative manner. Previously, it was not realistic to expose vascular endothelial cells to pollutants, as the lung is an effective barrier that scrubs all but the smallest amounts of most inhaled contaminants. Here, we have developed a model that allows for a realistic exposure in humans and then considers the outcomes related to the vascular endothelium that are central to progression of atherosclerosis and coagulation disorders. Although the immediate impact of showing a pro-atherosclerotic effect of 500 ppb nitrogen dioxide is not trivial, the development of this novel assay will have lasting repercussions on the field of environmental health.

Future Activities:

Thus, over the final year of this project we will round out the assays and integration of data for Aims 1 and 3. Although certain follow-up activities are planned related to the mechanistic findings of a role for LOX-1 in lipid peroxidation, those will be outside the scope of the current project.


Journal Articles on this Report : 6 Displayed | Download in RIS Format

Other project views: All 9 publications 6 publications in selected types All 6 journal articles
Type Citation Project Document Sources
Journal Article Campen MJ, Lund A, Rosenfeld M. Mechanisms linking traffic-related air pollution and atherosclerosis. Current Opinion in Pulmonary Medicine 2012;18(2):155-160. R833990 (2010)
R833990 (2011)
R834796 (2012)
R834796 (2013)
R834796 (2015)
R834796 (Final)
R834796C003 (2012)
R834796C003 (2013)
R834796C003 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Abstract: Lippincott Williams & Wilkins-Abstract
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  • Journal Article Channell MM, Paffett ML, Devlin RB, Madden MC, Campen MJ. 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 2012;127(1):179-186. R833990 (2010)
    R833990 (2011)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Abstract: Oxford Journals-Abstract
    Exit
  • Journal Article Kodavanti UP, Thomas R, Ledbetter AD, Schladweiler MC, Shannahan JH, Wallenborn JG, Lund AK, Campen MJ, Butler EO, Gottipolu RR, Nyska A, Richards JE, Andrews D, Jaskot RH, McKee J, Kotha SR, Patel RB, Parinandi NL. Vascular and cardiac Impairments in rats inhaling ozone and diesel exhaust particles. Environmental Health Perspectives 2011;119(3):312-318. R833990 (2009)
    R833990 (2010)
    R833990 (2011)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Abstract: EHP - Abstract & Full Text HTML
  • Journal Article Lund AK, Lucero J, Harman M, Madden MC, McDonald JD, Seagrave JC, Campen MJ. The oxidized low-density lipoprotein receptor mediates vascular effects of inhaled vehicle emissions. American Journal of Respiratory and Critical Care Medicine 2011;184(1):82-91. R833990 (2009)
    R833990 (2010)
    R833990 (2011)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: AJRCCM - Full Text PDF
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  • Abstract: AJRCCM - Abstract
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  • Journal Article Lund AK, Doyle-Eisele M, Lin Y-H, Arashiro M, Surratt JD, Holmes T, Schilling KA, Seinfeld JH, Rohr AC, Knipping EM, McDonald, JD. The effects of α-pinene versus toluene-derived secondary organic aerosol exposure on the expression of markers associated with vascular disease. Inhalation Toxicology 2013;25(6):309-324. R833990 (2011)
    R834796 (2013)
    R834796 (2014)
    R834796 (2015)
    R834796 (Final)
    R834796C002 (2015)
    R834796C002 (Final)
    R834796C003 (2013)
  • Abstract from PubMed
  • Abstract: Taylor & Francis-Abstract
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  • Other: UNC at Chapel Hill-Abstract
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  • Journal Article Robertson S, Colombo ES, Lucas SN, Hall PR, Febbraio M, Paffett ML, Campen MJ. CD36 mediates endothelial dysfunction downstream of circulating factors induced by O3 exposure. Toxicological Sciences 2013;134(2):304-311. R833990 (2011)
    R834796 (2013)
    R834796 (2014)
    R834796 (2015)
    R834796 (Final)
    R834796C003 (2013)
    R834796C003 (2016)
    R834796C003 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: Oxford Journals-Full Text HTML
    Exit
  • Abstract: Oxford Journals-Abstract
    Exit
  • Other: Oxford Journals-Full Text PDF
    Exit
  • Supplemental Keywords:

    RFA, Health, Scientific Discipline, Air, particulate matter, Health Risk Assessment, Risk Assessments, ambient air quality, atmospheric particulate matter, chemical characteristics, human health effects, cardiovascular vulnerability, biological mechanisms, chemical composition, biological mechanism , human exposure, ambient particle health effects, autonomic dysfunction, oxidative stress

    Progress and Final Reports:

    Original Abstract
  • 2009 Progress Report
  • 2010 Progress Report
  • Final