Atherothrombotic Effects of Particulate Matter

EPA Grant Number: EM833367
Title: Atherothrombotic Effects of Particulate Matter
Investigators: Bhatnagar, Aruni , Conklin, Daniel
Institution: University of Louisville
EPA Project Officer: Chung, Serena
Project Period: August 1, 2007 through July 31, 2010
Project Amount: $1,500,000
RFA: Targeted Research Grant (2007) Recipients Lists
Research Category: Targeted Research , Particulate Matter

Objective:

The overall goal of this project is to understand the mechanism by which ambient air particulate matter (PM) affects thrombosis and vascular responses in normal, diseased, and genetically-engineered mice. Our central hypothesis is that by inducing system inflammation, PM exposure causes abnormal activation of the endothelium, thereby distorting its response to injury and compromising the functional integrity of the vessel wall. We propose further that these changes are thrombogenic and vasoconstrictive and that they induce cardiovascular injury. Our objectives are to: (1) Determine acute thrombotic responses to concentrated ambient Louisville PM and (2) Elucidate the molecular mechanism underlying the vascular and systemic effects of PM.

Approach:

Using C57B1/6 and LDL-receptor-null mice, we will examine how exposure to Louisville concentrated ambient particles acutely affects inflammation, platelet activation and monocyte adhesion in normal and dyslipedemic mice. By measuring tissue-specific changes in transcription factors, (NF-kB, Nrf2, and MTF-1), we will assess the relative contribution of inflammation, oxidative stress, and metal toxicity to the overall vascular effects of PM. We will delineate specific cardiovascular sites where PM causes inflammation or oxidative stress and we will identify which specific components of PM or its gaseous copollutants correlate with acute thrombotic responses. To assess molecular mechanisms, we will determine whether specific features of vascular toxicity of PM in mice deficient in heme oxygenase-1 (HO-1), Nrf2, and metallothionein-1 (MT-1) or inducible nitric oxide synthase (iNOS) are altered and whether the oxidative effects of PM are diminished in mice over-expressing extracellular superoxide dismutase (ecSOD). In addition, to examine functional changes, we will measure blood pressure and vascular reactivity in animals exposed to filtered air and to concentrated ambient particles to determine how changes in molecular parameters of thrombosis and vascular inflammation affect cardiovascular health and function.

Expected Results:

Results obtained from this project will be useful in establishing the molecular and cellular mechanisms by which PM affects blood coagulation and thrombosis and acutely alters vasoreactivity. From these studies we will be able to establish whether dyslipedemia and lipid induced vascular inflammation could be a risk factor for the cardiovascular toxicity of PM. These studies will also help in elucidating the role of antioxidant defenses in determining susceptibility to PM and indentifying which pollutant gases or PM components are likely to be most strongly associated with individual features of cardiovascular injury relating to changes in blood pressure and coagulation.

Publications and Presentations:

Publications have been submitted on this project: View all 25 publications for this project

Journal Articles:

Journal Articles have been submitted on this project: View all 16 journal articles for this project

Supplemental Keywords:

Thrombosis, blood pressure, oxidative stress, transcription factors, particulate matter, air pollution, sensitive population,

Progress and Final Reports:

  • 2008 Progress Report
  • 2009 Progress Report
  • Final Report