Effect of Diesel Exhaust Particulate Exposures on Endothelial Function in Humans: The Role of Oxidative StressEPA Grant Number: R830954
Title: Effect of Diesel Exhaust Particulate Exposures on Endothelial Function in Humans: The Role of Oxidative Stress
Investigators: Kaufman, Joel D. , Chandler, Wayne , Gill, Edward , Koenig, Jane Q. , Larson, Timothy V. , Leotta, Daniel , Sheppard, Lianne (Elizabeth) A. , Sullivan, Jeff , Trenga, Carol , Yost, Michael
Institution: University of Washington
EPA Project Officer: Hunt, Sherri
Project Period: August 15, 2003 through August 14, 2006 (Extended to August 14, 2008)
Project Amount: $1,036,972
RFA: Airborne Particulate Matter Health Effects: Cardiovascular Mechanisms (2002) RFA Text | Recipients Lists
Research Category: Air Quality and Air Toxics , Particulate Matter , Air , Health Effects
This proposal addresses the overall hypothesis that ambient fine particulate matter exerts cardiovascular health effects via alteration of endothelial homeostasis through a mechanism mediated by oxidative stress. This project will use a controlled human inhalation exposure to diesel exhaust particulate (DEP) as a model to address the following objectives: 1) determine whether exposure to inhaled DEP is associated with endothelial dysfunction in a concentration-related manner; 2) determine whether exposure to inhaled DEP is associated with evidence of systemic oxidative stress; and 3) determine whether antioxidant supplementation blunts the DEP effect on endothelial function.
Three crossover experiments (each randomized, balanced with regard to order, and separated by appropriate washout interval) will expose healthy subjects to well-characterized DEP in two-hour sessions in an inhalation chamber system mimicking ambient particulate matter from contemporary diesel engines.
First, 24 subjects will be exposed to DEP at each of three concentrations [0 (filtered air, FA), 100, or 200 µg/m3], and endothelial function will be assessed post-exposure through ultrasonographic measurement of endothelial-dependent flow-mediated vasodilation of the brachial artery, plasma markers of endothelial homeostasis (endothelin-1, ICAM-1, e-selectin, NO3-/NO2-, IL-6, and TNF-a), and markers of thrombosis associated with endothelial activation (PAI-1, D-dimer, and VWF).
Second, 10 subjects will be exposed to FA or DEP at 200 µg/m3 and then monitored intensively in the clinical research center for evidence of systemic oxidative stress using serial assessment of markers in plasma (GSH/GSSG, TBARS, oxidized LDL, and ascorbate) and urine (isoprostane F-2a).
Finally, 24 subjects will be administered the antioxidants ascorbate and N-acetylcysteine, or placebos, and then exposed to DEP or FA in a double-blinded four-condition experiment, and subsequently assessed for endothelial function, to determine the effect of antioxidants on DEP's impact on endothelial function.
These experiments will provide valuable insight into 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.