There is epidemiological, clinical, and experimental data linking chronic and acute exposure to air pollution with morbidity and mortality from cardiovascular disease. The mechanisms by which pollutants such as diesel exhaust contribute to cardiovascular disease are unknown but multiple possibilities have been posited. These include responses to common molecular mediators elicited by the pollutants in the lungs. Small particulates have been shown to induce oxidative stress and expression of pro-inflammatory cytokines by many cell types within the lungs. It is likely therefore that this inflammatory response in the lungs also impacts the ongoing inflammation in the blood vessels. Inflammatory mechanisms are associated with both atherosclerotic lesion initiation and progression. Cytokines and other proinflammatory factors are expressed by leukocytes, endothelial cells, and smooth muscle cells in atherosclerotic lesions and are thought to contribute to the destabilization of the plaques by further inducing localized oxidant stress with consequent loss of nitric oxide mediated dilation, increasing expression and secretion of matrix metalloproteinases, and causing cell death. The death of macrophages and smooth muscle cells is largely responsible for the formation of the necrotic core and thinning of the fibrous cap. These changes in turn, reduce the tensile strength of the plaques and lead to plaque rupture, occlusive thrombosis and ischemia, the ultimate causes of myocardial infarction and stroke. In this proposal, the investigators will draw on their extensive experience with mouse models of unstable atherosclerosis and oxidant stress and their experience in measuring cardiac and vascular function in mice. They will investigate how acute and chronic exposures to diesel exhaust in a unique controlled exposure chamber impact on cytokine secretion, flow mediated dilation, the electrical properties of the heart and the progression and stability of advanced atherosclerofic lesions. The investigators will also directly address the role of oxidant stress in mediating the effects of diesel exhaust by employing unique mouse models that have either an increased capacity to produce the main endogenous antioxidant glutathione specifically in macrophages or conversely, mice that have a reduced capacity to produce glutathione.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES013434-02
Application #
6941233
Study Section
Special Emphasis Panel (ZES1-LKB-E (CA))
Program Officer
Mastin, Patrick
Project Start
2004-08-19
Project End
2008-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
2
Fiscal Year
2005
Total Cost
$360,940
Indirect Cost
Name
University of Washington
Department
Pathology
Type
Schools of Public Health
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Liu, Yonggang; Chien, Wei-Ming; Medvedev, Ivan O et al. (2013) Inhalation of diesel exhaust does not exacerbate cardiac hypertrophy or heart failure in two mouse models of cardiac hypertrophy. Part Fibre Toxicol 10:49
Bai, Ni; Tranfield, Erin M; Kavanagh, Terrance J et al. (2012) Exposure to diesel exhaust upregulates COX-2 expression in ApoE knockout mice. Inhal Toxicol 24:518-27
Bai, Ni; Kido, Takashi; Kavanagh, Terrance J et al. (2011) Exposure to diesel exhaust up-regulates iNOS expression in ApoE knockout mice. Toxicol Appl Pharmacol 255:184-92
Bai, Ni; Kido, Takashi; Suzuki, Hisashi et al. (2011) Changes in atherosclerotic plaques induced by inhalation of diesel exhaust. Atherosclerosis 216:299-306