Effect of diesel exhaust particulate exposures on endothelial function in humans: The role of oxidative stress EPA Grant Number: R830954 Principal investigator: Joel Kaufman, MD, MPH
This study hypothesizes that ambient fine particulate matter exerts cardiovascular health effects by altering endothelial homeostasis through a mechanism mediated by oxidative stress. This project uses a controlled human inhalation exposure to diesel exhaust particulate (DEP) as a model to determine: 1) whether exposure to inhaled DEP is associated with endothelial dysfunction in a concentration-related manner; 2) whether exposure to inhaled DEP is associated with evidence of systemic oxidative stress; and 3) whether antioxidant supplementation blunts the DEP effect on endothelial function. Randomly selected, healthy people will b e exposed to well-characterized DEP in two-hour sessions in an inhalation chamber system mimicking ambient particulate matter from contemporary diesel engines. After their exposure, they will be tested for endothelial function or systemic oxidative stress. The goals are to better understand a potential underlying mechanism of cardiovascular health effects of combustion-derived PM, and test a hypothesis that can explain both acute and chronic effects found in epidemiologic studies. Diesel Exhaust and Atherosclerotic Plaque Stability Grant number R01ES013434) Principal investigator: Michael Rosenfeld, PhD Epidemiological, clinical, and experimental data link chronic and acute exposure to air pollution with morbidity and mortality from cardiovascular disease. 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 that this inflammatory response in the lungs also affects blood vessels. Inflammatory mechanisms are associated with the initiation and progression of atherosclerotic lesions and the destabilization of plaques, which can ultimately cause myocardial infarction and stroke. This study investigates how acute and chronic exposures to diesel exhaust in a unique controlled exposure chamber affect cytokine secretion, flow mediated dilation, electrical properties of the heart, and the progression and stability of advanced atherosclerotic lesions. It uses 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. | 
