Particle Toxicity and the Respiratory Bronchiole

EPA Grant Number: R826246
Title: Particle Toxicity and the Respiratory Bronchiole
Investigators:
Institution: University of California - Davis
EPA Project Officer: Hunt, Sherri
Project Period: February 1, 1998 through January 31, 2001
Project Amount: $525,000
RFA: Health Effects and Exposures to Particulate Matter and Associated Air Pollutants (1997) RFA Text |  Recipients Lists
Research Category: Air Quality and Air Toxics , Particulate Matter , Air , Health Effects

Description:

The goal of this proposal is to examine the mechanisms of particulate toxicity in the lungs of rats and monkeys following short (1-3 day) and long-term (28 day) exposure to particles that directly impact on epithelial cells of the airways, respiratory bronchioles, and alveoli. Since epithelial cells are the first cells in the respiratory tract to come into contact with inhaled particles, we hypothesize that damage to these cells can serve as a direct and highly sensitive measure of particle toxicity. We hypothesize that epithelial cells lining the transitional zone between the airways and gas exchange regions of the lungs (i.e., the respiratory bronchiole) are particularly sensitive and play a key role in the initiation and progression of particle-induced pulmonary injury. We further hypothesize that epithelial-particle interactions initiate a cascade of events that underlie the adverse effects associated with inhaled particles. We hypothesize that particle toxicity begins with the depletion of cellular glutathione levels in epithelial cells, thus accentuating cytotoxic events leading to cell death. In turn, cell death begins the process of cellular proliferation. Each of these events impact negatively on the ability of the lungs to translocate and clear particles, thus leading to further irritation and injury. We will test each of these hypotheses using novel approaches to examine epithelial cell structure and function throughout the airways and alveoli.

Approach:

State-of-the-art techniques to measure epithelial cytotoxicity, proliferation, antioxidant capacity and epithelial particle clearance will be used. The sensitivity of epithelial cells to particulate matter will be determined by airway location and generation within the tracheobronchial tree of both the rat and the monkey. We hypothesize that the pattern of particle deposition is pivotal to the degree of injury measured in the lungs. A systematic approach will be taken to initially expose rats to different concentrations of selected components associated with urban PM, including carbon and ammonium sulfate. Subsequent exposures will be performed in monkeys. Exposure to particles will be short (1-3 day) and long-term (28 day) at concentrations which are environmentally relevant. The duration of particle exposure will be used to establish dose-response curves using well-defined biological endpoints. The effects of co-exposure of particles with ozone will also be examined to determine the potential for interactive effects in what should constitute a better simulation of "real-world" exposure conditions.

Expected Results:

Those mechanisms by which particles may exert an adverse effect(s) on the cardiopulmonary system should be identified to better define the current human epidemiologic data on PM10 effects. The importance of the respiratory bronchiole in particle deposition, translocation, and retention/clearance and associated particle-induced lung injury will be directly examined in two animal models to better extrapolate our findings to humans.

Publications and Presentations:

Publications have been submitted on this project: View all 9 publications for this project

Journal Articles:

Journal Articles have been submitted on this project: View all 9 journal articles for this project

Supplemental Keywords:

Health Effects, Particulate Matter, Air Pollution, Sensitive Populations, Sulfates., RFA, Health, Scientific Discipline, Air, particulate matter, Toxicology, Health Risk Assessment, Risk Assessments, Biochemistry, human health effects, inhalability, epithelial cells, human airway epithelial calls, cytotoxic events, respiratory bronchiole, cellular mechanisms, lung inflammation, particulate exposure, pulmonary, human exposure, animal toxicological studies, tracheobronchial tree, PM

Progress and Final Reports:

2000 Progress Report
Final Report