Grantee Research Project Results
2005 Progress Report: Coronary Effects of Combustion-Source Particulate Matter
EPA Grant Number: R830839Title: Coronary Effects of Combustion-Source Particulate Matter
Investigators: Campen, Matthew J. , McDonald, Jacob D. , Reed, Matthew D.
Institution: Lovelace Biomedical & Environmental Research Institute
EPA Project Officer: Chung, Serena
Project Period: April 21, 2003 through April 20, 2006 (Extended to March 31, 2007)
Project Period Covered by this Report: April 21, 2005 through April 20,2006
Project Amount: $1,018,920
RFA: Airborne Particulate Matter Health Effects: Cardiovascular Mechanisms (2002) RFA Text | Recipients Lists
Research Category: Particulate Matter , Air Quality and Air Toxics , Human Health , Air
Objective:
Ambient levels of particulate matter (PM) air pollution within attainment of current National Ambient Air Quality Standards have been associated with cardiovascular morbidity and mortality in many epidemiological studies. Although a causal relationship between PM and cardiovascular morbidity is implicated, a concrete mechanism has not yet been demonstrated. A recent report demonstrated systemic vasoconstriction following inhalation of environmentally relevant levels of combined PM and ozone, whereas other evidence has specifically linked myocardial infarction with acute PM exposure. Therefore, the primary objective of this research project will be to examine the in vivo and in vitro effects of particles on coronary artery physiology. We hypothesize that PM could adversely affect cardiac function in two ways: (1) directly, via soluble constituents of PM that access the circulation and alter vascular physiology, potentially disrupting dilatory responses or even leading to vasospasm and myocardial infarction; and (2) indirectly by PM-induced inflammation that impairs the basic function of the cardiopulmonary system (i.e., gas exchange) and thus predisposes the myocardium to hypoxemic conduction anomalies. We therefore propose to investigate indices of risk for vasospastic sudden cardiac death and alterations in coronary artery physiology incurred by exposure to combustion-source (diesel exhaust) particles and associated gaseous co-pollutants in a murine model of coronary vascular disease.
Progress Summary:
In the first group of studies, we compared electrocardiographic effects of fresh gasoline engine emissions, resuspended paved road dust, and diesel exhaust from an engine operating on a high load and one operating on a low load using a mouse model of coronary insufficiency. Apolipoprotein E-deficient (ApoE-/-) mice on a high-fat diet were exposed by whole-body inhalation to either gasoline emissions at 60 μg/m3 particulate matter (PM), an equivalent atmosphere with particles filtered out of the whole exhaust, or paved road dust or diesel exhaust at 0.5 and 3.5 mg PM/m3 for 6 hours/day for 3 days. Radiotelemetry recordings of ECG were analyzed for changes in T-wave morphology (QT interval, T-wave amplitude, and T-wave area). Following exposures, lung lavage and blood samples were obtained to assay for markers of pulmonary and systemic inflammation. Exposure to gasoline emissions and road dust induced no significant change in heart rate and only the high concentration of road dust induced signs of pulmonary inflammation. Diesel, on the other hand, produced marked bradycardia and arrhythmogenesis; the emissions during low load operation appeared to potentiate this response. T-wave area exhibited significant deviation from baseline values during exposure to gasoline exhaust particulates, but not to either concentration of road dust or gasoline emissions sans particulates. Gasoline-exposed mice demonstrated elevated plasma endothelin-1 but did not show systemic inflammation. These data support the hypothesis that freshly-generated engine emissions, as opposed to resuspended paved road dust, may drive cardiac effects that have been observed at road-sides in the environment. The absence of ECG effects for both very high concentrations of road dust PM and equivalent concentrations of the vapor/gas phase of gasoline engine exhaust further indicate the specific risk conferred by fresh vehicular PM.
The second study was a bit of a divergence from the earlier work on acute effects. Epidemiological evidence indicates that environmental air pollutants are positively associated with the development of chronic vascular disease; however, the mechanisms involved have not been fully elucidated. In this study we examined molecular pathways associated with chronic vascular disease in atherosclerosis-prone ApoE-/- mice, including markers of vascular remodeling and oxidative stress, in response to exposure to the ubiquitous environmental pollutant, gasoline engine emissions. ApoE-/- mice, on a high-fat diet, were exposed by inhalation to either filtered air; 8, 40, or 60 μg/m3 PM whole exhaust; or filtered exhaust with gases matching the 60 μg/m3 concentration for 7 weeks. Aortas and plasma were collected and assayed for changes in histochemical markers, real-time reverse transcription-PCR, and indicators of oxidative damage. Inhalational exposure to gasoline engine emissions resulted in increased aortic mRNA expression of matrix metalloproteinase-3, -7, and -9, tissue inhibitor of metalloproteinases-2, endothelin-1 and heme oxygenase-1 in ApoE-/- mice; increased aortic MMP-9 protein levels were confirmed through immunohistochemistry. Elevated reactive oxygen species also were observed in arteries from exposed animals, despite absence of plasma markers. Similar findings were also observed in the aortas of ApoE-/- mice exposed to particle-filtered atmosphere, implicating the gaseous components of the whole exhaust in mediating the expression of markers associated with the vasculopathy. These findings demonstrate that exposure to gasoline engine emissions results in the transcriptional upregulation of factors associated with vascular remodeling, as well as increased markers of vascular oxidative stress, which may contribute to the progression of atherosclerosis and reduced stability of vulnerable plaques.
In the third study, we investigated the acute changes in these markers of vascular remodeling in the presence and absence of Tempol, a cell-permeable superoxide dismutase mimetic, and BQ-123, an endothelin receptor A antagonist. The results obtained remain unpublished and preliminary, but exposures resulted in a time-dependent increase in aortic expression of MMP-2 and -9, and endothelin-1 mRNA. Furthermore, aortic TIMP2 mRNA expression was significantly increased as early as a single day exposure; this effect was fully antagonized by Tempol treatment. HO-1, on the other hand, was significantly reduced by exposure. Whereas Tempol attenuated responses with MMPs and TIMPs, it had no apparent effect on ET-1 or HO-1 alterations. We continue to explore these endpoints in the BQ-123 tissues.
Future Activities:
We will complete analysis of several collected tissues from past exposures and analyze ECG data in greater detail.
Journal Articles on this Report : 6 Displayed | Download in RIS Format
| Other project views: | All 22 publications | 6 publications in selected types | All 6 journal articles |
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Campen MJ, Babu NS, Helms GA, Pett S, Wernly J, Mehran R, McDonald JD. Nonparticulate components of diesel exhaust promote constriction in coronary arteries from ApoE-/-mice. Toxicological Sciences 2005;88(1):95-102. |
R830839 (2004) R830839 (2005) R830839 (Final) |
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Campen MJ, McDonald JD, Reed MD, Seagrave JC. Fresh gasoline emissions, not paved road dust, alter cardiac repolarization in ApoE-/- mice. Cardiovascular Toxicology 2006;6(3-4):199-209. |
R830839 (2005) R830839 (Final) CR831455 (Final) |
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Lund AK, Knuckles TL, Akata CO, Shohet R, McDonald JD, Gigliotti A, Seagrave JC, Campen MJ. Gasoline exhaust emissions induce vascular remodeling pathways involved in atherosclerosis. Toxicological Sciences 2007;95(2):485-494. |
R830839 (2005) R830839 (Final) CR831455 (Final) R831860 (2007) R831860 (Final) |
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Lund AK, Lucero J, Lucas S, Madden MC, McDonald JD, Seagrave J-C, Knuckles TL, Campen MJ. Vehicular emissions induce vascular MMP-9 expression and activity associated with endothelin-1–mediated pathways. Arteriosclerosis, Thrombosis, and Vascular Biology 2009;29(4):511-517. |
R830839 (2005) R830839 (Final) CR831455 (Final) |
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McDonald JD, Reed MD, Campen MJ, Barrett EG, Seagrave JC, Mauderly JL. Health effects of inhaled gasoline engine emissions. Inhalation Toxicology 2007;19(Suppl 1):107-116. |
R830839 (2005) |
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Rowan III WH, Campen MJ, Wichers LB, Watkinson WP. Heart rate variability in rodents: uses and caveats in toxicological studies. Cardiovascular Toxicology 2007;7(1):28-51. |
R830839 (2005) R830839 (Final) CR831455 (Final) |
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Supplemental Keywords:
atherosclerosis, coronary artery disease, carbon monoxide, gasoline engine emissions, road dust, air pollution, nitrogen dioxide,, RFA, Health, Air, Scientific Discipline, TREATMENT/CONTROL, Health Risk Assessment, Risk Assessments, particulate matter, Incineration/Combustion, Air Pollution Control, air toxics, health effects, inhaled, combustion-related pollutants, stratospheric ozone, combustion emissions, fine particles, lung inflammation, oxidant gas, acute lung injury, cardiopulmonary responses, particulate exposure, abatement, acute exposure, Acute health effects, cardiotoxicity, copollutant exposures, airway epithelial cells, cardiac arrest, chronic health effects, susceptible subpopulations, concentrated particulate matter, atmospheric particulate matter, cardiopulmonary effects, cardiovascular morbifity, vascoconstriction, air pollution, cardiopulmonary, cardiovascular disease, elderly adults, airborne urban contaminants, acute cardiovascular effectsProgress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.