2000 Progress Report: Particle Toxicity and the Respiratory Bronchiole

EPA Grant Number: R826246
Title: Particle Toxicity and the Respiratory Bronchiole
Institution: University of California - Davis
EPA Project Officer: Chung, Serena
Project Period: February 1, 1998 through January 31, 2001
Project Period Covered by this Report: February 1, 1999 through January 31, 2000
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


The overall objective of this project is to examine the mechanisms of particle toxicity in the lungs of rats and monkeys following short-term (3-day) exposure to particles that impact directly on epithelial cells of the airways, respiratory bronchiles, and alveoli. Because 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) particularly are 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 that lead to cell death. In turn, cell death begins the process of cellular proliferation. Each of these events impacts 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 by using novel approaches to examine epithelial cell structure and function throughout the airways and alveoli.

Progress Summary:

Ambient exposure to particulate matter (PM) has been associated with a variety of adverse health effects involving the cardiopulmonary system. However, the biological mechanisms to explain how PM exposure increases or may even cause these effects are unknown. This study is designed to determine if exposure to ammonium nitrate (AN) and carbon (C), two common components found in California PM, will affect the respiratory tract of healthy adult rats. Sprague Dawley rats have been exposed to filtered air (FA), PM (150 µg/m3 AN and 200 µg/m3 C), ozone (0.2 ppm), or PM plus ozone for 6 hours/day for 3 days. Epithelial cell permeability and reduced gluthathione levels (GSH) were used as biomarkers of effects along the airways and lung parenchyma. Bronchoalveolar lavage (BAL) also was used to determine lung cellular responses following exposure. Cellular proliferation measured by bromodeoxyuridine (BrdU) uptake was examined within site-specific regions of the airways and lung parenchyma. Following particle exposure, epithelial cell permeability was markedly increased at airway bifurcations. GSH levels, although different for each anatomical site examined, were not changed significantly by exposure to PM and/or ozone compared with controls. BAL following exposure to PM demonstrated a 73 percent increase in number above control value. BrdU-labeled epithelial cells were increased two-fold above control values at airway bifurcations following exposure to PM and PM plus ozone compared with FA controls, but were unchanged along the airways. Interstitial cell labeling at airway bifurcations also was increased significantly following exposure to PM plus ozone. Significant increases in BrdU labeling within central acinar regions of the lungs also were noted for all treatments groups compared with FA controls. These findings suggest that: (1) AN and C cause injury to the lungs, (2) these effects are independent of ozone, and (3) airway bifurcations and central acini are important sites of injury to inhaled PM.

Exposure to AN and C for 6 hours/day for 3 days was repeated using Rhesus monkeys. Exposure conditions were similar between monkeys and rats. Cellular proliferation measured by BrdU uptake was examined in the respiratory bronchioles of each monkey and found to be increased significantly following PM exposure (2.4 ? 0.4 percent in controls and 4.1?1.2 percent in animals exposed to PM). These findings further substantiate a significant particle effect within critical site-specific regions of the lungs across two different species?the rat and the monkey.

Future Activities:

Future activities include extending our understanding of PM effects on the respiratory tract of rodents to nonhuman primates.

Journal Articles on this Report : 1 Displayed | Download in RIS Format

Other project views: All 11 publications 11 publications in selected types All 11 journal articles
Type Citation Project Document Sources
Journal Article Dietert RR, Etzel RA, Chen D, Halonen M, Holladay SD, Jarabek AM, Landreth K, Peden DB, Pinkerton K, Smialowicz RJ, Zoetis T. Workshop to identify critical windows of exposure for children's health: immune and respiratory systems work group summary. Environmental Health Perspectives 2000;108(Suppl 3):483-490. R826246 (2000)
R827995 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • 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, human exposure, lung inflammation, pulmonary, particulate exposure, PM, animal toxicological studies, tracheobronchial tree

    Relevant Websites:

    http://www.envtox.ucdavis.edu/cehs/Exit EPA icon
    http://agcenter.ucdavis.edu/agcenter/Exit EPA icon

    Progress and Final Reports:

    Original Abstract
  • 1998
  • 1999
  • Final Report