Grantee Research Project Results
Final Report: Adjuvant Effects of Ozone in a Model of Allergen-Induced Airway Inflammation and Hyperresponsiveness
EPA Grant Number: R825702C012Subproject: this is subproject number 012 , established and managed by the Center Director under grant R825702
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: Denver Children’s Environmental Health Center - Environmental Determinants of Airway Disease in Children
Center Director: Schwartz, David A.
Title: Adjuvant Effects of Ozone in a Model of Allergen-Induced Airway Inflammation and Hyperresponsiveness
Investigators: Gelfand, Erwin
Institution: National Jewish Medical and Research Center
EPA Project Officer: Chung, Serena
Project Period: February 16, 1998 through February 28, 2003 (Extended to February 28, 2004)
RFA: Environmental Lung Disease Center (National Jewish Medical and Research Center) (1998) RFA Text | Recipients Lists
Research Category: Targeted Research
Objective:
The objectives of this research project were to: (1) identify the kinetics of the response to ozone exposure; (2) define the role of complement activation in the response to ozone; and (3) determine the role of neutrophils in the airway response to ozone.
Summary/Accomplishments (Outputs/Outcomes):
Using C57Bl/6 mice, we showed that acute exposure to ozone elicited a rapid, dose-dependent response characterized by early neutrophil influx, rapid epithelial desquamation, and increased airway responsiveness to methacholine (MCh). Responses were maximum at 1-2 ppm O3 for 3-hour exposures and fell off rapidly at 0.5 ppm. Airway hyperresponsiveness (AHR) peaked at 24 hrs, with return to baseline by 48-72 hrs. Airway inflammation rapidly resolved. Remarkably, airway epithelial repaving/repair was seen by 24 hours and by 48 hours ciliated epithelial cells were observed.
We evaluated the role of complement in the development of AHR and inflammation after acute O3 exposure using complement depletion or inhibition. Between 8 and 24 hours after O3 exposure, a three-fold increase in bronchoalveolar lavage (BAL) levels of C3a was detected, suggesting that O3 exposure leads to complement activation.
Depletion of complement with cobra venom factor before O3 exposure significantly reduced AHR as well as total cell numbers, neutrophilia, and eosinophils in BAL fluid. Similar results were obtained in mice treated with complement receptor gene y-Ig, a potent C3 convertase inhibitor. These data suggested that acute O3 exposure leads to complement activation and this activation is responsible for the development of AHR and airway inflammation. To determine if the reduction in lung inflammation, and neutrophils in particular, was related to the changes in airway function, mice were administered an antineutrophil antibody prior to O3 exposure, which reduced the neutrophil response by more than 90 percent. Despite this reduction, O3-induced AHR was unaffected. Similarly, lung epithelial cell desquamation was also unaffected (Park, et al., 2004a).
Given the acute inflammatory response to O3 exposure, we examined the role of IL-1, a multifunctional proinflammatory cytokine. Exposure of C57Bl/6 mice to O3 induced strong IL-1β gene transcription as well as increased levels of IL-1β in lung homogenates. Administration of an IL-1R antagonist prevented the development of AHR, damage to the epithelial cell surface, and airway neutrophilia. Of interest, administration of dexamethasone markedly reduced development of AHR, IL-1β and airway neutrophilia (Park, et al., 2004b).
Importance to the Scientific Community
Acute exposure to O3 is known to induce alterations in lung function and airway inflammation. In these studies, we have shown that acute exposure to O3 triggers three distinct and seemingly independent events: epithelial desquamation, increased airway responsiveness to inhaled MCh, and airway neutrophilia. Both complement activation and generation of IL-1β appear to be important mediators of the responses. Conceivably, complement activation and release of activated products C3a and C5a attract inflammatory cells capable of releasing increased quantities of IL-1, which leads to the characteristic pathology and alterations in airway function.
Importance to the U.S. Environmental Protection Agency
O3 is recognized as an important toxic oxidant in the workplace and in urban environments. This study confirmed that acute effects of O3 in mice require a high level of O3, 0.5 ppm or greater. The mechanism of toxicity at these high doses includes complement activation and increased levels of IL-1β. The remarkable finding was how rapid the airway epithelium recovered after injury. The demonstration that administration of a glucocorticoid can reduce significantly the toxic effects of O3 exposure on epithelial cell integrity and airway responsiveness, perhaps through preventing increases in IL-1β, is of clinical importance.
Journal Articles on this Report : 20 Displayed | Download in RIS Format
Other subproject views: | All 24 publications | 20 publications in selected types | All 20 journal articles |
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Other center views: | All 132 publications | 111 publications in selected types | All 110 journal articles |
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Cui Z-H, Joetham A, Aydintug MK, Hahn Y-S, Born WK, Gelfand EW. Reversal of allergic airway hyperreactivity after long-term allergen challenge depends on γδ T cells. American Journal of Respiratory and Critical Care Medicine 2003;168(11):1324-1332. |
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Dakhama A, Kraft M, Martin RJ, Gelfand EW. Induction of regulated upon activation, normal T cells expressed and secreted (RANTES) and transforming growth factor-β1 in airway epithelial cells by Mycoplasma pneumoniae. American Journal of Respiratory Cell and Molecular Biology 2003;29(3):344-351. |
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Dakhama A, Larsen GL, Gelfand EW. Calcitonin gene-related peptide: role in airway homeostasis. Current Opinion in Pharmacology 2004;4(3):215-220. |
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Gelfand EW, Joetham A, Cui Z-H, Balhorn A, Takeda K, Taube C, Dakhama A. Induction and maintenance of airway responsiveness to allergen challenge are determined at the age of initial sensitization. Journal of Immunology 2004;173(2):1298-1306. |
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Haczku A, Takeda K, Hamelmann E, Loader J, Joetham A, Redai I, Irvin CG, Lee JJ, Kikutani H, Conrad D, Gelfand EW. CD23 exhibits negative regulatory effects on allergic sensitization and airway hyperresponsiveness. American Journal of Respiratory and Critical Care Medicine 2000;161(3):952-960. |
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Hamelmann E, Takeda K, Haczku A, Cieslewicz G, Shultz L, Hamid Q, Xing Z, Gauldie J, Gelfand EW. Interleukin (IL)-5 but not immunoglobulin E reconstitutes airway inflammation and airway hyperresponsiveness in IL-4-deficient mice. American Journal of Respiratory Cell and Molecular Biology 2000;23(3):327-334. |
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Kanehiro A, Takeda K, Joetham A, Tomkinson A, Ikemura T, Irvin CG, Gelfand EW. Timing of administration of anti-VLA-4 differentiates airway hyperresponsiveness in the central and peripheral airways in mice. American Journal of Respiratory and Critical Care Medicine 2000;162(3):1132-1139. |
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Kanehiro A, Ikemura T, Makela MJ, Lahn M, Joetham A, Dakhama A, Gelfand EW. Inhibition of phosphodiesterase 4 attenuates airway hyperresponsiveness and airway inflammation in a model of secondary allergen challenge. American Journal of Respiratory and Critical Care Medicine 2001;163(1):173-184. |
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Kanehiro A, Lahn M, Makela MJ, Dakhama A, Joetham A, Rha Y-H, Born W, Gelfand EW. Requirement for the p75 TNF-α receptor 2 in the regulation of airway hyperresponsiveness by γδ T cells. Journal of Immunology 2002;169(8):4190-4197. |
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Kodama T, Kuribayashi K, Nakamura H, Fujita M, Fujita T, Takeda K, Dakhama A, Gelfand EW, Matsuyama T, Kitada O. Role of interleukin-12 in the regulation of CD4+ T cell apoptosis in a mouse model of asthma. Clinical and Experimental Immunology 2003;131(2):199-205. |
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Larsen GL, White CW, Takeda K, Loader JE, Nguyen DDH, Joetham A, Groner Y, Gelfand EW. Mice that overexpress Cu/Zn superoxide dismutase are resistant to allergen-induced changes in airway control. American Journal of Physiology-Lung Cellular and Molecular Physiology 2000;279(2):L350-L359. |
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Makela MJ, Kanehiro A, Dakhama A, Borish L, Joetham A, Tripp R, Anderson L, Gelfand EW. The failure of interleukin-10-deficient mice to develop airway hyperresponsiveness is overcome by respiratory syncytial virus infection in allergen-sensitized/challenged mice. American Journal of Respiratory and Critical Care Medicine 2002;165(6):824-831. |
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Makela MJ, Tripp R, Dakhama A, Park J-W, Ikemura T, Joetham A, Waris M, Anderson LJ, Gelfand EW. Prior airway exposure to allergen increases virus-induced airway hyperresponsiveness. The Journal of Allergy and Clinical Immunology 2003;112(5):861-869. |
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Park J-W, Taube C, Joetham A, Takeda K, Kodama T, Dakhama A, McConville G, Allen CB, Sfyroera G, Schultz LD, Lambris JD, Giclas PC, Holers VM, Gelfand EW. Complement activation is critical to airway hyperresponsiveness after acute ozone exposure. American Journal of Respiratory and Critical Care Medicine 2004;169(6):726-732. |
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Park JW, Taube C, Yang ES, Joetham A, Balhorn A, Takeda K, Miyahara N, Dakhama A, Donaldson DD, Gelfand EW. Respiratory syncytial virus-induced airway hyperresponsiveness is independent of IL-13 compared with that induced by allergen. The Journal of Allergy and Clinical Immunology 2003;112(6):1078-1087. |
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Park J-W, Taube C, Swasey C, Kodama T, Joetham A, Balhorn A, Takeda K, Miyahara N, Allen CB, Dakhama A, Kim S-H, Dinarello CA, Gelfand EW. Interleukin-1 receptor antagonist attenuates airway hyperresponsiveness following exposure to ozone. American Journal of Respiratory Cell and Molecular Biology 2004;30(6):830-836. |
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Rha Y-H, Taube C, Haczku A, Joetham A, Takeda K, Duez C, Siegel M, Aydintug MK, Born WK, Dakhama A, Gelfand EW. Effect of microbial heat shock proteins on airway inflammation and hyperresponsiveness. Journal of Immunology 2002;169(9):5300-5307. |
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Sun W, Kesavan K, Schaefer BC, Garrington TP, Ware M, Johnson NL, Gelfand EW, Johnson GL. MEKK2 associates with the adapter protein Lad/RIBP and regulates the MEK5-BMK1/ERK5 pathway. Journal of Biological Chemistry 2001;276(7):5093-5100. |
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Taube C, Nick JA, Siegmund B, Duez C, Takeda K, Rha Y-H, Park J-W, Joetham A, Poch K, Dakhama A, Dinarello CA, Gelfand EW. Inhibition of early airway neutrophilia does not affect development of airway hyperresponsiveness. American Journal of Respiratory Cell and Molecular Biology 2004;30(6):837-843. |
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Tomkinson A, Duez C, Cieslewicz G, Pratt JC, Joetham A, Shanafelt M-C, Gundel R, Gelfand EW. A murine IL-4 receptor antagonist that inhibits IL-4-and IL-13-induced responses prevents antigen-induced airway eosinophilia and airway hyperresponsiveness. Journal of Immunology 2001;166(9):5792-5800. |
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Supplemental Keywords:
air toxics, acute lung injury, air pollutants, airway disease, animal studies, environmental toxicant, exposure, genetic susceptibility, health effects, human exposure, human health risk, lung disease, lung epithelial cells, occupational disease, occupational exposure,, RFA, Scientific Discipline, Health, PHYSICAL ASPECTS, Air, particulate matter, Epidemiology, Risk Assessments, Biochemistry, Physical Processes, Atmospheric Sciences, Biology, chemical exposure, Nitrogen dioxide, particulates, human health effects, animal model, ozone, exposure, air pollution, particle exposure, particle exposure models, environmental health effects, inhalation, human exposure, particulate exposure, exposure core, inhaled, PM, human health riskRelevant Websites:
Progress and Final Reports:
Original AbstractMain Center Abstract and Reports:
R825702 Denver Children’s Environmental Health Center - Environmental Determinants of Airway Disease in Children Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R825702C001 SP-A and SP-D in Environmental Lung Disease
R825702C003 Adaptation to Nitrogen Dioxide: Role of Altered Glycolytic Pathway Enzyme Expression and NF-κB-Dependent Cellular Defenses Against Apoptosis
R825702C005 Inhalation of Particulate Matter Alters the Allergic Airway Response to Inhaled Allergen
R825702C006 Particle-Induced Lung Inflammation and Extracellular EC-SOD
R825702C007 Indoor-Outdoor Relationships of Airborne Particle Count and Endotoxin Concentrations
R825702C008 The Role of Mitochondrial DNA Mutations in Oxidant-Mediated Lung Injury
R825702C009 Immunopathogenesis of Hypersensitivity Pneumonitis in the Mouse
R825702C010 Activation of Natural T Lymphocytes by Diesel Exhaust Particulates Leads to Their Production of Interleukin-4 and TH2 Lymphocyte Differentiation to Allergen
R825702C011 Latex Antigen Levels During Powdered and Powderless Glove Use
R825702C012 Adjuvant Effects of Ozone in a Model of Allergen-Induced Airway Inflammation and Hyperresponsiveness
R825702C013 Acute Exposure to Particulate Air Pollution in Childhood Asthma
R825702C014 Mechanisms of Ozone Toxicity to the Lung
The 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.
Project Research Results
20 journal articles for this subproject
Main Center: R825702
132 publications for this center
110 journal articles for this center