Grantee Research Project Results

Project 2: The Role of Oxidative Stress in PM-induced Adverse Health Effects

EPA Grant Number: R832413C002
Subproject: this is subproject number 002 , established and managed by the Center Director under grant R832413
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: Great Lakes Air Center for Integrative Environmental Research
Center Director: Harkema, Jack
Title: Project 2: The Role of Oxidative Stress in PM-induced Adverse Health Effects
Investigators: Nel, Andre E. , Kleinman, Michael T. , Lusis, Aldons , Harkema, Jack
Institution: University of California - Los Angeles , Michigan State University , University of California - Irvine
EPA Project Officer: Chung, Serena
Project Period: October 1, 2005 through September 30, 2010 (Extended to September 30, 2012)
RFA: Particulate Matter Research Centers (2004) RFA Text | Recipients Lists
Research Category: Human Health , Air

Objective:

The primary objective is to elucidate the mechanisms of PM-induced asthma and atherosclerosis exacerbation. Our principal hypothesis is that PM-induced oxidative stress initiates airway and arterial wall inflammation. We propose that the biological response to oxidative stress is a hierarchical event, in which the induction of antioxidant defense at the lowest tier (Tier 1) of oxidative stress protects against the pro-inflammatory (Tier 2) and cytotoxic effects (Tier 3) of higher levels of oxidative stress. Integral to this hypothesis is the proposal that a weakened antioxidant defense may define disease susceptibility.

Approach:

In Aim 1, we will use normal and genetically susceptible murine models to study the role of oxidative stress in PM-induced exacerbation of asthma and atherosclerosis. We will use low grade OVA sensitization to study the effects of fine and ultrafine particles (UFP) on allergic airway inflammation, oxidative stress, IgE production, mucus hypersecretion, and airway hyperreactivity (AHR) in a BALB/c model. We will use Nrf2 knockout mice, with a weakened antioxidant response, to determine whether this will enhance airway inflammation. A third component of this Aim will be to use atherosclerosis-prone apoE knockout mice to assess dose-dependent atherogenesis and oxidative modification of LDL and HDL during CAPS exposure. In Aim 2, we will use in vitro toxicology approaches to assess the effects of various PM sources, with unique and varying chemical composition, on the induction of oxidative stress and inflammatory responses in tissue culture macrophages, epithelial and endothelial cells. This study will use coarse, fine and UFP, collected at different sites and during different seasons (Project 1), to determine their effects on: (i) phase II enzyme expression by Western blotting and real-time PCR (Tier 1); (ii) cytokine and chemokine expression as determined by ELISA assays and protein arrays (Tier 2); (iii) perturbation of mitochondrial function and induction of apoptosis as determined by flow cytometry and functional studies on isolated mitochondria (Tier 3). These biological responses will be compared to the chemical composition of the particles (Project 1), their activity in the chemical reactivity assays (Project 3), and their ability to promote asthma and atherosclerosis in animal models. In Aim 3, we will use serum samples, collected from indoor-exposed elderly human subjects with ischemic heart disease (Project 4), to determine how oxidative modification of HDL affects its anti-inflammatory and atheroprotective effects. We will assess how the increase in oxidized phospholipids in LDL affects its pro-inflammatory effects in an endothelial co-culture assay. We will determine whether oxidative modification of HDL-associated paraoxonase activity modifies its anti-inflammatory effects in this assay.

Expected Results:

We expect that due to the presence of redox cycling chemicals, ambient PM induce a series of pro-oxidative and pro-inflammatory effects which enhance asthma and atherosclerosis. We expect that these effects will be related to particle dose, size, source, composition, and season, and will be exaggerated in individuals and animals with a weakened antioxidant defense. This study will yield important biomarkers that will be linked to specific toxicological components that could be monitored to prevent adverse health effects.

Publications and Presentations:

Publications have been submitted on this subproject: View all 34 publications for this subproject | View all 241 publications for this center

Journal Articles:

Journal Articles have been submitted on this subproject: View all 23 journal articles for this subproject | View all 157 journal articles for this center

Supplemental Keywords:

Ambient air, health effects, biology, sensitive populations, human health, animal, PAH,, RFA, Health, Scientific Discipline, Air, particulate matter, Toxicology, Health Risk Assessment, Risk Assessments, Biochemistry, Ecology and Ecosystems, particulates, atmospheric particulate matter, human health effects, PM 2.5, airway disease, cardiovascular vulnerability, animal model, airborne particulate matter, air pollution, human exposure, vascular dysfunction, cardiovascular disease, human health risk

Progress and Final Reports:

Main Center Abstract and Reports:

R832413 Great Lakes Air Center for Integrative Environmental Research

Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R832413C001 Contribution of Primary and Secondary PM Sources to Exposure & Evaluation of Their Relative Toxicity
R832413C002 Project 2: The Role of Oxidative Stress in PM-induced Adverse Health Effects
R832413C003 The Chemical Properties of PM and their Toxicological Implications
R832413C004 Oxidative Stress Responses to PM Exposure in Elderly Individuals With Coronary Heart Disease
R832413C005 Ultrafine Particles on and Near Freeways

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The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.