Extramural Research
Presentation Abstract
Grantee Research Project Results
Michael E. Rosenfeld
University of Washington, Seattle, WA
NIEHS Grant Number: 1R01ES013434-01
Project Description:
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.