Grantee Research Project Results
Final Report: Cellular Mechanisms of Pulmonary Inflammation by Environmental Particles
EPA Grant Number: R824790Title: Cellular Mechanisms of Pulmonary Inflammation by Environmental Particles
Investigators:
Institution: Harvard University
EPA Project Officer: Chung, Serena
Project Period: October 1, 1995 through September 30, 1998
Project Amount: $546,895
RFA: Air Pollutants (1995) RFA Text | Recipients Lists
Research Category: Air Quality and Air Toxics , Air
Objective:
Health effects of air particles occur most notably among individuals with pre-existing respiratory disease, e.g. COPD and asthma, indicating a heightened sensitivity to particle effects within inflamed lungs. This research project sought to test the hypothesis that pre-existing pulmonary disease amplifies or 'primes' the response of lung macrophages and epithelial cells to inhaled particles, resulting in increased inflammation and health effects. The project began with the following specific aims: #1.) Characterize the phlogistic effects of concentrated ambient particulates (CAPs) on lung cells 'primed' by inflammatory mediators; #2.) Characterize the effects of inhaled concentrated ambient particulates (CAPs) on pre-existing inflammatory lung disease using an in vivo asthma model; and #3.) Identify pathogenic components within concentrated ambient particles.Summary/Accomplishments (Outputs/Outcomes):
- Inflammatory priming substantially increase cytokine production by lung macrophages and epithelial cells exposed to air particles in vitro
- There is substantial variability from day-to-day in air particles' ability to activate inflammatory mediator production by lung cells
- Both water-soluble (leachate) and solid-phase components of air particle samples can activate lung cells, with complex differences depending on cell type, cytokine measured and day of sampling
- Trace endotoxin synergizes with intrinsic particle features in activation of lung macrophages in vitro
- In vivo exposures of a mouse model of asthma to CAPs did not show any enchancement of asthma under the conditions of these exposures; additional studies using co-exposure to ozone are underway
Conclusions:
The major findings support the hypothesis that inflammatory priming of lung cells enhances and amplifies additional inflammatory responses to air particles. We studied both alveolar macrophages and lung epithelial cells. For both major cell types, we found that pre-exposure to inflammatory cytokines (e.g., TNF for lung epithelial cells) or endotoxin for alveolar macrophages substantially amplifies their production of inflammatory mediators when the 'primed' cells are challenged with air particles in vitro.We were also able to use the in vitro systems to analyze which components of air particle samples contribute to their pathogenicity. These findings show a rich complexity, with macrophages and epithelial cells differing in their relative activation by the water-soluble (metal-rich) leachates of particles vs. the solid particle fraction. We have also identified an important synergy of particles with trace endotoxin present in the solid phase that contributes to activation of normal cells in vitro.
The in vivo experiments did not show any clear effect of aerosol exposure to CAPs on the physiologic or pathologic phenotype of a murine model of asthma employed in this study. We are presently evaluating the effects of co-exposure to ozone as well as CAPs on this model, building on the database established by this project.
Journal Articles on this Report : 9 Displayed | Download in RIS Format
| Other project views: | All 10 publications | 9 publications in selected types | All 9 journal articles |
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Goldsmith CA, Frevert C, Imrich A, Sioutas C, Kobzik L. Alveolar macrophage interaction with air pollution particulates. Environmental Health Perspectives 1997;105(Suppl 5):1191-1195. |
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Goldsmith CA, Imrich A, Danaee H, Ning Y, Kobzik L. Analysis of air pollution particulate-mediated oxidant stress in alveolar macrophages. Journal of Toxicology and Environmental Health-Part A 1998;54(7):529-545. |
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Goldsmith CA, Hamada K, Ning YY, Qin GZ, Catalano P, Murthy GGK, Lawrence J, Kobzik L. Effects of environmental aerosols on airway hyperresponsiveness in a murine model of asthma. Inhalation Toxicology 1999;11(11):981-998. |
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Goldsmith C-AW, Ning YY, Qin G, Imrich A, Lawrence J, Murthy GGK, Catalano PJ, Kobzik L. Combined air pollution particle and ozone exposure increases airway responsiveness in mice. Inhalation Toxicology 2002;14(4):325-347. |
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Imrich A, Ning YY, Kobzik L. Intracellular oxidant production and cytokine responses in lung macrophages: evaluation of fluorescent probes. Journal of Leukocyte Biology 1999;65(4):499-507. |
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Imrich A, Ning YY, Koziel H, Coull B, Kobzik L. Lipopolysaccharide priming amplifies lung macrophage tumor necrosis factor production in response to air particles. Toxicology and Applied Pharmacology 1999;159(2):117-124. |
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Ning YY, Imrich A, Goldsmith CA, Qin GZ, Kobzik L. Alveolar macrophage cytokine production in response to air particles in vitro: role of endotoxin. Journal of Toxicology and Environmental Health-Part A 2000;59(3):165-180. |
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Stringer B, Imrich A, Kobzik L. Lung epithelial cell (A549) interaction with unopsonized environmental particulates: Quantitation of particle-specific binding and IL-8 production. Experimental Lung Research 1996;22(5):495-508. |
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Stringer B, Kobzik L. Environmental particulate-mediated cytokine production in lung epithelial cells (A549): role of preexisting inflammation and oxidant stress. Journal of Toxicology and Environmental Health-Part A 1998;55(1):31-44. |
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Supplemental Keywords:
RFA, Scientific Discipline, Air, Geographic Area, particulate matter, Health Risk Assessment, Environmental Chemistry, air toxics, State, Atmospheric Sciences, EPA Region, ambient aerosol, particle size, human health effects, concentrated ambient particulates (CAPs), morbidity, respiration, exposure and effects, pulmonary disease, epithelial cells, air pollution, Massachusetts (MA), cellular mechanisms, human exposure, lung inflammation, particulate exposure, inhaled, mortality, pathogenesisProgress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.