2011 Progress Report: Cardiovascular Consequences of Immune Modification by Traffic-Related Emissions

EPA Grant Number: R834796C003
Subproject: this is subproject number 003 , established and managed by the Center Director under grant R834796
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: University of Washington Center for Clean Air Research
Center Director: Vedal, Sverre
Title: Cardiovascular Consequences of Immune Modification by Traffic-Related Emissions
Investigators: Campen, Matthew J. , Lund, Amie K. , McDonald, Jacob D. , Rosenfeld, Michael
Current Investigators: Campen, Matthew J. , McDonald, Jacob D. , Rosenfeld, Michael
Institution: Lovelace Respiratory Research Institute , University of New Mexico , University of Washington
Current Institution: University of New Mexico , Lovelace Respiratory Research Institute , University of Washington , Washington State University
EPA Project Officer: Callan, Richard
Project Period: December 1, 2010 through November 30, 2015 (Extended to November 30, 2017)
Project Period Covered by this Report: December 1, 2010 through July 31,2011
RFA: Clean Air Research Centers (2009) RFA Text |  Recipients Lists
Research Category: Health Effects , Air

Objective:

Traffic-related emissions are associated with the incidence and progression of acute and chronic cardiovascular sequelae in human population studies. Such phenomena of near-roadway health effects have yet to be characterized toxicologically. Because of potentially complex confounding issues related to noise, socioeconomic status, ethnicity, etc., there is a need to better understand the biological underpinnings of the hypothesis that fresh mixtures of vehicular emissions have a more potent than expected impact on human health. We hypothesize that the complex mixtures produced by traffic are inherently more toxic due to the combined presence of both particulates and volatile organic emissions. Furthermore, we hypothesize that emissions-induced oxidation of certain endogenous phospholipids, presumably from the pulmonary surfactant, can stimulate the activity of immune cells through such receptors and in turn promote the invasion of existing vascular lesions. This project will use complex roadway mixtures as generated and characterized in the laboratory (Project 2) to pursue the following aims:

Aim 1: Ascertain 1) the potentiating effects of physical and photochemical aging on fresh emissions and 2) interactions of vehicular emissions with pertinent copollutants (ozone, road dust) driving systemic vascular oxidative stress.
 
Aim 2: Examine effects of the emissions-induced oxidative modifications to endogenous phospholipids in activating immune-modulating receptors such as LOX-1, CD-36, TLR-2, and TLR-4. This Aim will utilize transgenic models to examine the roles of these receptors, as well as characterize the lipidomic alterations in various tissues.
 
Aim 3: Further explore the role of specific immune cell populations as participants in the innate and adaptive responses to emissions-induced phospholipid modifications. Here we utilize mouse models of immunodeficiency, including SCID and B-Cell deficient models. Additionally, we will pursue bone-marrow transplants from mice lacking those receptors described in Aim 2 to mechanistically establish the involvement of the oxidatively-modified phospholipids.
 
Findings will 1) indicate the most potent combinations of urban roadway and background copollutants in terms of vascular toxicity and 2) detail the role of the immune system in mechanistically driving the systemic effects of inhaled pollutants.

Progress Summary:

At present, we have ordered the first cohort of mice for exposures. We are planning to carry out the first profile of exposures, detailed in Aim 1, in July-September 2011.

The first pilot studies are slated to begin late July 2011, in which we will start assessing the interactions between vehicular source pollutants (gasoline and diesel engine emissions) in driving vascular oxidative stress. Three ratios of emission composition will be tested among two strains (ApoE-null and LDLR-null) of mice and two diets (high fat and normal). Results from these early studies will focus efforts for future work in Aims 2 and 3. All exposures will be carried out using standardized exposure protocols established in Project 2.

After an initial delay, due in part to overlapping commitments in the engine rooms, we are on target to begin a series of weeklong exposures and to transfer tissues to the respective investigators for expedited biological assays in the Fall 2011-Spring 2012 timeframe.

Future Activities:

To complete accelerated exposures pertaining to Aim 1, and the vascular injury assays from those exposed animals, and complete breeding of double knockout mice. Continue interactions with Projects 1 and 2 in refining the exposure conditions.

Journal Articles:

No journal articles submitted with this report: View all 20 publications for this subproject

Supplemental Keywords:

Coronary artery disease, oxidized phospholipids, atherosclerosis, particulate matter, volatile organic compounds, VOCs, carbon monoxide, ozone, toxicology, Scientific Discipline, Health, Air, ENVIRONMENTAL MANAGEMENT, Air Quality, air toxics, Health Risk Assessment, Risk Assessments, mobile sources, Environmental Monitoring, Biochemistry, Risk Assessment, ambient air quality, atmospheric particulate matter, particulate matter, aerosol particles, air pollutants, motor vehicle emissions, vehicle emissions, air quality models, motor vehicle exhaust, airway disease, bioavailability, air pollution, particle exposure, atmospheric aerosols, ambient particle health effects, vascular dysfunction, cardiotoxicity, atmospheric chemistry, exposure assessment

Progress and Final Reports:

Original Abstract
2012 Progress Report
2013 Progress Report
2015 Progress Report
2016 Progress Report


Main Center Abstract and Reports:

R834796    University of Washington Center for Clean Air Research

Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R834796C001 Exposure Mapping – Characterization of Gases and Particles for ExposureAssessment in Health Effects and Laboratory Studies
R834796C002 Simulated Roadway Exposure Atmospheres for Laboratory Animal and Human Studies
R834796C003 Cardiovascular Consequences of Immune Modification by Traffic-Related Emissions
R834796C004 Vascular Response to Traffic-Derived Inhalation in Humans
R834796C005 Effects of Long-Term Exposure to Traffic-Derived Particles and Gases on Subclinical Measures of Cardiovascular Disease in a Multi-Ethnic Cohort