Grantee Research Project Results
2008 Progress Report: Project 2: The Role of Oxidative Stress in PM-induced Adverse Health Effects
EPA Grant Number: R832413C002Subproject: 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)
Project Period Covered by this Report: October 1, 2007 through September 30,2008
RFA: Particulate Matter Research Centers (2004) RFA Text | Recipients Lists
Research Category: Human Health , Air
Objective:
The primary objective is to elucidate the mechanism(s) of PM-induced asthma and atherosclerosis exacerbation in vitro and in vivo. This is accomplished by animal studies in the mobile trailer in downtown Los Angeles as well as in vitro studies in representative tissue culture cells. The principal hypothesis is that a major PM injury mechanism is the induction of ROS production and oxidative stress that promotes respiratory and cardiovascular inflammation as the major pathology feature underlying asthma and atherosclerosis (Nel 2005; Xia et al 2006a, 2006b; Nel et al 2006). We propose that oxidative stress is a hierarchical event in which the induction of antioxidant defense pathways in tier 1 is in dynamic equilibrium and defends against the pro-inflammatory (tier 2) pro-apoptotic (tier 3) effects of higher levels of oxidative stress (Nel et al 2006).
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.
Progress Summary:
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.
Future Activities:
Journal Articles on this Report : 10 Displayed | Download in RIS Format
Other subproject views: | All 34 publications | 23 publications in selected types | All 23 journal articles |
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Other center views: | All 241 publications | 157 publications in selected types | All 157 journal articles |
Type | Citation | ||
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Araujo JA, Barajas B, Kleinman M, Wang X, Bennett BJ, Gong KW, Navab M, Harkema J, Sioutas C, Lusis AJ, Nel AE. Ambient particulate pollutants in the ultrafine range promote early atherosclerosis and systemic oxidative stress. Circulation Research 2008;102(5):589-596. |
R832413 (2008) R832413 (2009) R832413 (2010) R832413 (Final) R832413C001 (2008) R832413C001 (Final) R832413C002 (2007) R832413C002 (2008) R832413C002 (2009) R832413C002 (Final) R832413C003 (Final) |
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Ayres JG, Borm P, Cassee FR, Castranova V, Donaldson K, Ghio A, Harrison RM, Hider R, Kelly F, Kooter IM, Marano F, Maynard RL, Mudway I, Nel A, Sioutas C, Smith S, Baeza-Squiban A, Cho A, Duggan S, Froines J. Evaluating the toxicity of airborne particulate matter and nanoparticles by measuring oxidative stress potential—a workshop report and consensus statement. Inhalation Toxicology 2008;20(1):75-99. |
R832413 (2008) R832413 (2009) R832413 (Final) R832413C001 (2007) R832413C001 (2008) R832413C001 (Final) R832413C002 (2008) R832413C003 (2008) R832413C003 (2009) |
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Chan RC-F, Wang M, Li N, Yanagawa Y, Onoe K, Lee JJ, Nel AE. Pro-oxidative diesel exhaust particle chemicals inhibit LPS-induced dendritic cell responses involved in T-helper differentiation. Journal of Allergy and Clinical Immunology 2006;118(2):455-465. |
R832413 (2008) R832413C002 (2007) R832413C002 (2008) R832413C002 (Final) R827352 (Final) R827352C002 (Final) |
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Chatila TA, Li N, Garcia-Lloret M, Kim H-J, Nel AE. T-cell effector pathways in allergic diseases:transcriptional mechanisms and therapeutic targets. Journal of Allergy and Clinical Immunology 2008;121(4):812-823. |
R832413 (2007) R832413 (2008) R832413 (2010) R832413 (Final) R832413C002 (2007) R832413C002 (2008) R832413C002 (2009) |
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Gong KW, Zhao W, Li N, Barajas B, Kleinman M, Sioutas C, Horvath S, Lusis AJ, Nel A, Araujo JA. Air-pollutant chemicals and oxidized lipids exhibit genome-wide synergistic effects on endothelial cells. Genome Biology 2007;8(7):R149 (13 pp.). |
R832413 (2008) R832413 (2009) R832413 (Final) R832413C001 (2008) R832413C001 (Final) R832413C002 (2007) R832413C002 (2008) R832413C002 (Final) |
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Li N, Nel AE. The cellular impacts of diesel exhaust particles:beyond inflammation and death. European Respiratory Journal 2006;27(4):667-668. |
R832413 (2008) R832413 (Final) R832413C002 (2006) R832413C002 (2008) |
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Li N, Xia T, Nel AE. The role of oxidative stress in ambient particulate matter-induced lung diseases and its implications in the toxicity of engineered nanoparticles. Free Radical Biology and Medicine 2008;44(9):1689-1699. |
R832413 (2007) R832413 (2008) R832413 (2010) R832413 (Final) R832413C002 (2007) R832413C002 (2008) R832413C002 (2009) |
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Xia T, Kovochich M, Brant J, Hotze M, Sempf J, Oberley T, Sioutas C, Yeh JI, Wiesner MR, Nel AE. Comparison of the abilities of ambient and manufactured nanoparticles to induce cellular toxicity according to an oxidative stress paradigm. Nano Letters 2006;6(8):1794-1807. |
R832413 (2008) R832413 (2009) R832413 (Final) R832413C001 (2007) R832413C001 (2008) R832413C001 (Final) R832413C002 (2006) R832413C002 (2008) R827352 (Final) R827352C002 (Final) R827352C014 (Final) |
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Xia T, Kovochich M, Nel A. The role of reactive oxygen species and oxidative stress in mediating particulate matter injury. Clinics in Occupational and Environmental Medicine 2006;5(4):817-836. |
R832413 (2008) R832413 (Final) R832413C002 (2007) R832413C002 (2008) |
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Xia T, Kovochich M, Nel AE. Impairment of mitochondrial function by particulate matter (PM) and their toxic components: implications for PM-induced cardiovascular and lung disease. Frontiers in Bioscience 2007;12(4):1238-1246. |
R832413 (2008) R832413 (Final) R832413C002 (2007) R832413C002 (2008) |
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Supplemental Keywords:
Ambient air, health effects, biology, sensitive populations, human health, animal, PAH,, RFA, Health, Scientific Discipline, Air, Toxicology, particulate matter, Health Risk Assessment, Risk Assessments, Biochemistry, Ecology and Ecosystems, atmospheric particulate matter, particulates, human health effects, PM 2.5, animal model, airway disease, airborne particulate matter, cardiovascular vulnerability, air pollution, human exposure, vascular dysfunction, cardiovascular disease, human health riskProgress and Final Reports:
Original AbstractMain 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
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.
Project Research Results
- Final Report
- 2011
- 2010 Progress Report
- 2009 Progress Report
- 2007 Progress Report
- 2006 Progress Report
- Original Abstract
23 journal articles for this subproject
Main Center: R832413
241 publications for this center
157 journal articles for this center