Responses to Fresh Aerosol in Susceptible SubjectsEPA Grant Number: R832144
Title: Responses to Fresh Aerosol in Susceptible Subjects
Investigators: Kipen, Howard , Fan, Tina , Laskin, Deborah , Laumbach, Robert , Lioy, Paul J. , Ohman-Strickland, Pamela , Philipp, Claire , Shindler, Daniel , Zhang, Junfeng
Institution: Robert Wood Johnson Medical School , Rutgers, The State University of New Jersey , University of Medicine and Dentistry of New Jersey
Current Institution: Robert Wood Johnson Medical School
EPA Project Officer: Hunt, Sherri
Project Period: October 1, 2004 through September 30, 2008
Project Amount: $1,521,398
RFA: The Role of Air Pollutants in Cardiovascular Disease (2003) RFA Text | Recipients Lists
Research Category: Air Quality and Air Toxics , Health Effects , Particulate Matter , Air
Increased occurrence of unstable angina and myocardial infarction, particularly in individuals vulnerable from preexisting atherosclerotic cardiovascular disease (ASCVD), follow even hourly increases in particulate air pollution. The mechanisms underlying these acute cardiovascular effects are unknown. Thrombosis, closely related to endothelial cell dysfunction and platelet activation, is now widely recognized to play an important role in acute exacerbations of cardiovascular disease. In experimental studies, endothelial changes are observed within minutes following a two hour exposure of humans to inhaled particulate air pollution. Similarly, platelet activation and thrombosis are observed in rodents within 30 minutes of intratracheal instillation of various ultrafine particles. In these models, both the endothelial and platelet responses appear to be independent of lung inflammation, suggesting an immediate and direct effect of ultrafine particles on these cells. The overall objective of our studies is to explore mechanisms mediating acute particle-induced prothrombotic effects. We hypothesize that the acute increase in risk of cardiac events following inhalation of ultrafine and fine particles is mediated by a rapid and direct passage of the particles from the lung into the blood, leading immediately to platelet activation and endothelial dysfunction, measured by a decrease in brachial artery reactivity. Moreover individuals with genetically increased risk for ASCVD and endothelial dysfunction due to a single nucleotide polymorphism (SNP) in endothelial Nitric Oxide Synthase (eNOS) will be more sensitive to these effects of ultrafine and fine particles on the endothelium.
To test this hypothesis we will use pollutant models of 200 mcg/m3 freshly generated diesel exhaust (DE) or a secondary organic aerosol (SOA) both of which consist predominately of particles less than one micron in diameter. The effects of the two fine and ultra fine aerosols, using a clean air control, will be compared in 25 young healthy normal individuals and 25 healthy individuals who are selected for the SNP.
We hypothesize that the DE will lead to increased markers of platelet activation and decreased brachial artery reactivity within 2 hours of the onset of exposure, in the absence of lung inflammation as measured by sputum induction, but that lung inflammation will be detectable at 6 hours after exposure. We expect that the SOA will not produce the same degree of thrombotic response due to its chemically different composition from the DE.