Final Report: 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: Chung, Serena
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

Objective:

The overall objective of this research project was to examine the mechanisms of particle toxicity in the lungs of rats and monkeys following short-term (3-day) exposure to particles that directly impact epithelial cells of the airways, respiratory bronchioles, and alveoli. Because epithelial cells are the first cells in the respiratory tract to be exposed to inhaled particles, we hypothesized that damage to these cells can serve as a direct and highly sensitive measure of particle toxicity. We hypothesized 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 hypothesized that epithelial-particle interactions initiate a cascade of events that underlie the adverse effects associated with inhaled particles. We also hypothesized 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 have a negative impact on the ability of the lungs to translocate and clear particles, thus leading to further irritation and injury. We tested each of these hypotheses using novel approaches to examine epithelial cell structure and function throughout the airways and alveoli.

Summary/Accomplishments (Outputs/Outcomes):

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 cause these effects are unknown. This study was 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 microgram/m3 AN and 200 microgram/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 significantly changed by exposure to PM and/or ozone compared with controls. BAL following exposure to PM demonstrated a 73 percent increase in the number above control value. BrdU-labeled epithelial cells were significantly increased twofold 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 significantly increased following exposure to PM plus ozone. Significant increases in BrdU labeling within central acinar regions of the lungs also was noted for all treatment 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 significantly increased 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.

Repeated 3-day exposure to AN and C leads to alterations in the normal homeostasis of the lungs in healthy rats and monkeys. These changes can occur either in the presence or absence of simultaneous exposure to ozone. These effects were noted as elevated numbers of cells recovered from the lungs by BAL. In general, alteration in the normal homeostasis of the lungs following exposure to airborne AN/C particles appears to be triggered in the healthy rat when the concentration of AN reaches or exceeds 150 µg/m3 and the C concentration reaches or exceeds 195 µg/m3. These studies confirm that rats can serve as reasonable animal models to investigate the effects of PM on the respiratory tract. Mixtures of AN and C, common components of California PM, evoke cellular changes in the lungs under conditions that could occur under high ambient concentrations in California. These findings confirm that measures of biological effect can be used to determine short-term responses to PM exposure. These findings further support the need for additional studies in toxicology to better define the mechanisms of PM-related health effects. This study also emphasizes the importance of age- and dose-related effects to airborne particles as well as the importance of studying the long-term implications of chronic exposure to PM. The relevance to public health of this research lies in the fact that rats exposed for the short term to AN and C experienced subtle, but significant respiratory effects in all ages studied. Therefore, it also is possible that human exposure to particles of composed of AN and C could have similar consequences.


Journal Articles on this Report : 10 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 Hyde DM, Miller LA, McDonald RJ, Stovall MY, Wong V, Pinkerton KE, Wegner CD, Rothlein R, Plopper CG. Neutrophils enhance clearance of necrotic epithelial cells in ozone-induced lung injury in rhesus monkeys. American Journal of Physiology—Lung Cellular and Molecular Physiology 1999;277(6):L1190-L1198. R826246 (Final)
  • Abstract from PubMed
  • Full-text: AJP-Full Text HTML
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  • Other: AJP-Full Text PDF
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  • Journal Article Madl AK, Wilson DW, Segall HJ, Pinkerton KE. Alteration in lung particle translocation, macrophage function, and microfilament arrangement in monocrotaline-treated rats. Toxicology and Applied Pharmacology 1998;153(1):28-38. R826246 (Final)
  • Abstract from PubMed
  • Full-text: Science Direct-Full Text PDF
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  • Abstract: Science Direct-Abstract
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  • Journal Article Ngo MA, Pinkerton KE, Freeland S, Geller M, Ham W, Cliff S, Hopkins LE, Kleeman MJ, Kodavanti UP, Meharg E, Plummer L, Recendez JJ, Schenker MB, Sioutas C, Smiley-Jewell S, Haas C, Gutstein J, Wexler AS. Airborne particles in the San Joaquin Valley may affect human health. California Agriculture 2010;64(1):12-16. R826246 (Final)
    R832413 (Final)
    R832413C001 (2010)
    R832413C001 (Final)
    R832414 (2010)
    R832414C003 (2010)
    R832414C003 (Final)
  • Full-text: CaliforniaAgriculture-Full Text PDF
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  • Abstract: CaliforniaAgriculture-Abstract and Full Text HTML
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  • Journal Article Pinkerton KE, Joad JP. The mammalian respiratory system and critical windows of exposure for children's health. Environmental Health Perspectives 2000;108(Suppl 3):457-462. R826246 (Final)
    R827995 (Final)
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  • Journal Article Pinkerton KE, Green FHY, Saiki C, Vallyathan V, Plopper CG, Gopal V, Hung D, Bahne EB, Lin SS, Menache MG, Schenker MB. Distribution of particulate matter and tissue remodeling in the human lung. Environmental Health Perspectives 2000;108(11):1063-1069. R826246 (Final)
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  • Journal Article Schelegle ES, Gershwin LJ, Miller LA, Fanucchi MV, Van Winkle LS, Gerriets JP, Walby WF, Omlor AM, Buckpitt AR, Tarkington BK, Wong VJ, Joad JP, Pinkerton KB, Wu R, Evans MJ, Hyde DM, Plopper CG. Allergic asthma induced in Rhesus monkeys by house dust mite (Dermatophagoides farinae). American Journal of Pathology 2001;158(1):333-341. R826246 (Final)
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  • Journal Article Schenker MB, Pinkerton KE, Mitchell D, Vallyathan V, Elvine-Kreis B, Green FHY. Pneumoconiosis from agricultural dust exposure among young California farmworkers. Environmental Health Perspectives 2009;117(6):988-994. R826246 (Final)
    R832414 (2010)
    R832414C003 (2009)
    R832414C003 (2010)
    R832414C003 (Final)
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  • Journal Article Smith KR, Kim S, Recendez JJ, Teague SV, Menache MG, Grubbs DE, Sioutas C, Pinkerton KE. Airborne particles of the California Central Valley alter the lungs of healthy adult rats. Environmental Health Perspectives 2003;111(7):902-908 (discussion A408-409). R826246 (Final)
    R827995 (Final)
    R829215 (Final)
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  • Full-text: EHP-Full Text PDF
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  • Journal Article Yang G, Teague S, Pinkerton K, Kennedy IM. Synthesis of an ultrafine iron and soot aerosol for the evaluation of particle toxicity. Aerosol Science and Technology 2001;35(3):759-766. R826246 (Final)
    R827995 (Final)
  • Full-text: Taylor and Francis-Full Text PDF
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  • Abstract: Taylor and Francis-Abstract
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  • Journal Article Zhou Y-M, Zhong C-Y, Kennedy IM, Pinkerton KE. Pulmonary responses of acute exposure to ultrafine iron particles in healthy adult rats. Environmental Toxicology 2003;18(4):227-235. R826246 (Final)
    R827995 (Final)
    R829215 (2003)
    R829215 (2004)
    R829215 (Final)
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  • Supplemental Keywords:

    health effects, particulate matter, PM, air pollution, sensitive populations, nitrates, 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
    http://agcenter.ucdavis.edu/agcenter/ Exit

    Progress and Final Reports:

    Original Abstract
  • 1998
  • 1999