PROJECT 2: THE ROLE OF OXIDATIVE STRESS IN PM-INDUCED ADVERSE HEALTH EFFECTS
Impact/Purpose:
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.
Description:
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.
Record Details:
Record Type:PROJECT(
ABSTRACT
)
Start Date:10/01/2005
Completion Date:09/30/2010
Record ID:
144563
Keywords:
AMBIENT AIR, HEALTH EFFECTS, BIOLOGY, SENSITIVE POPULATIONS, HUMAN HEALTH, ANIMAL, PAH,
Related Organizations:
Role
:OWNER
Organization Name
:MICHIGAN STATE UNIVERSITY
Organization Name
:SCPC
Role
:OWNER
Organization Name
:UNIVERSITY OF CALIFORNIA - LOS ANGELES
Organization Name
:SCPC
Role
:OWNER
Organization Name
:UNIVERSITY OF CALIFORNIA - IRVINE
Organization Name
:SCPC
Project Information:
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 h
Cost
:$.00
Research Component
:Health Effects
Project IDs:
ID Code
:R832413C002
Project type
:Center