Air pollution is positively associated with an increased daily incidence of myocardial infarction and cardiovascular mortality. Recent findings strongly implicate a role for fresh vehicular exhaust, clearly showing elevated coronary events related acutely to traffic exposure. Clinical and experimental research suggests that air pollutants can acutely induce a vasoconstrictive mechanism, though a clear connection between such studies and the ultimate cardiac sequelae has not been confirmed. The proposed study will seek to validate our previous observations that specific gaseous components of engine exhaust, which are a significant contributor to ambient air pollution, may have pathological vasoactive properties by blunting coronary dilation and enhancing constriction. ECG and vascular abnormalities in ApoE-/- mice occurred when exposed by inhalation to fresh diesel or gasoline exhaust, but not aged, resuspended road dust, suggest that certain compounds in fresh emissions that drive cardiovascular responses may be lost in collected or concentrated particles. Many volatile and semivolatile compounds in fresh emissions can exist in both the gaseous and particulate phases of whole exhaust, and it may be that attempts to ascertain toxicity of filter-collected or concentrated PM may underestimate the adverse health effects by eliminating the gaseous co-pollutants. We have three primary hypotheses to test in this study: (1) We hypothesize that gaseous components of whole emissions can exert effects directly on vascular tissue as well as indirectly by oxidatively modifying endogenous circulating phospholipids, thereby altering the native function of those lipids. Our findings of oxidized low density lipoprotein in the circulation and lipid peroxidation by-products in the vasculature of engine emission-exposed mice, in the absence of overt pulmonary or systemic inflammation suggests that there may be a mild oxidative process in the lung that transfers systemically;(2) We hypothesize that the predominant mechanism driving impaired dilatory function is the formation of peroxynitrite and uncoupling of endothelial nitric oxide synthase. Nitrotyrosine is upregulated in the vasculature following chronic, low-level gasoline exhaust exposure, but it is unknown to what degree peroxynitrite impacts acutely on the vessels;and (3) We hypothesize that observed T-wave abnormalities reflect emission-induced impairment of endothelial cell function, leading to diminished coronary flow and myocardial ischemia in vulnerable subjects. Findings of air pollution-induced rat and mouse ECG abnormalities from several laboratories have not been validated in terms of absolute cardiovascular pathology;we predict diminished coronary flow and mild ischemia will occur in the susceptible mouse strain (ApoE-/-).

Public Health Relevance

Cardiovascular effects of air pollution are becoming recognized as a major public health concern. These studies will examine both biological and chemical mechanisms of air pollution-induced adverse coronary events. Results from these studies will assist in the assessment and management of personal risk of health effects from air pollution exposure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES014639-06
Application #
8254448
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Nadadur, Srikanth
Project Start
2008-05-01
Project End
2013-09-24
Budget Start
2012-03-01
Budget End
2013-09-24
Support Year
6
Fiscal Year
2012
Total Cost
$329,277
Indirect Cost
$108,754
Name
University of New Mexico
Department
Other Health Professions
Type
Schools of Pharmacy
DUNS #
868853094
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
Campen, Matthew; Robertson, Sarah; Lund, Amie et al. (2014) Engine exhaust particulate and gas phase contributions to vascular toxicity. Inhal Toxicol 26:353-60
Campen, Matthew J; Lund, Amie; Rosenfeld, Michael (2012) Mechanisms linking traffic-related air pollution and atherosclerosis. Curr Opin Pulm Med 18:155-60
Campen, Matthew J (2012) Vascular endothelium as a target of diesel particulate matter-associated toxicants. Arch Toxicol 86:517-8
Seilkop, Steven K; Campen, Matthew J; Lund, Amie K et al. (2012) Identification of chemical components of combustion emissions that affect pro-atherosclerotic vascular responses in mice. Inhal Toxicol 24:270-87
Paffett, Michael L; Channell, Meghan M; Naik, Jay S et al. (2012) Cardiac and vascular atrogin-1 mRNA expression is not associated with dexamethasone efficacy in the monocrotaline model of pulmonary hypertension. Cardiovasc Toxicol 12:226-34
Paffett, Michael L; Lucas, Selita N; Campen, Matthew J (2012) Resveratrol reverses monocrotaline-induced pulmonary vascular and cardiac dysfunction: a potential role for atrogin-1 in smooth muscle. Vascul Pharmacol 56:64-73
Channell, Meghan M; Paffett, Michael L; Devlin, Robert B et al. (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. Toxicol Sci 127:179-86
McDonald, Jacob D; Campen, Matthew J; Harrod, Kevin S et al. (2011) Engine-operating load influences diesel exhaust composition and cardiopulmonary and immune responses. Environ Health Perspect 119:1136-41
Knuckles, Travis L; Buntz, Jennifer G; Paffett, Michael et al. (2011) Formation of vascular S-nitrosothiols and plasma nitrates/nitrites following inhalation of diesel emissions. J Toxicol Environ Health A 74:828-37
Cherng, Tom W; Paffett, Michael L; Jackson-Weaver, Olan et al. (2011) Mechanisms of diesel-induced endothelial nitric oxide synthase dysfunction in coronary arterioles. Environ Health Perspect 119:98-103

Showing the most recent 10 out of 15 publications