Although there is extensive epidemiological evidence that acute exposure to particulate pollutants is associated with cardiorespiratory mortality, we lack understanding of the components and the mechanisms by which particulate matter (PM) induce these effects. PM contain a complex mixture of organic and inorganic compounds and innovative research tools needs to be developed to identify xenobiotics responsible for adverse health effects. Our principal hypothesis is that polycyclic aromatic hydrocarbons (PAH) including oxy-derivatives induce biological effects through the induction of redox stress. In this proposal we will focus on diesel exhaust particles (DEP) as a model PM, which induce pro-inflammatory effects and apoptosis in macrophages and epithelial cells in vivo and in vitro.
In Aim I we will fractionate DEP into major aromatic and polar chemical fractions for the purpose of determining the contribution of PAHs and oxy-PAHs to oxidative stress generation in vitro. This goal will be accomplished by silica gel column chromatography, analytical GC/MS and subfractionation procedures to identify functionalized PAHs and oxy-PAHs by oxidative stress and cellular apoptosis assays.
In Aim 2, we will use macrophages and epithelial cells to study the role of oxidative stress signaling pathways in the generation of pro-inflammatory responses by aromatic and polar DEP chemicals. We will determine whether generation of oxidative stress by functionalized PAHs from select DEP sources play a role in the production of cytokines and chemokines involved in airway inflammation. We will determine how the activation of NF-KB and AP-l response elements by ROS play a role in inducing the promoters of the RANTES and lL-8 genes. We will demonstrate that oxidative stress is involved in the pro-inflammatory effects of DEP or concentrated PM in humans and mice.
iii Aim 3, we will study the cytotoxic effects of polar and aromatic DEP fractions and their subfractions in vivo and vitro. This includes effects on cellular apoptosis, via mitochondrial perturbation. We will determine whether macrophages and toxic granular proteins from eosinophils synergize with DEP in epithelial damage, a contributory cause to airway hyperactivity in asthmatics. We will determine if inhaled ambient PM induce apoptosis in induced sputum samples in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES010553-04
Application #
6839480
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Tinkle, Sally S
Project Start
2002-02-21
Project End
2006-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
4
Fiscal Year
2005
Total Cost
$305,000
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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