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Final Report: Immunologic Basis of Environmental Lung Disease
EPA Grant Number: R825702Center: Environmental Lung Disease Center (National Jewish Medical and Research Center)
Center Director: Mason, Robert
Title: Immunologic Basis of Environmental Lung Disease
Investigators: Mason, Robert J. , Gelfand, Erwin , Rabinovitch, Nathan , White, Carl W.
Institution: National Jewish Medical and Research Center
EPA Project Officer: Glenn, Barbara
Project Period: February 16, 1998 through February 28, 2003 (Extended to February 28, 2004)
Project Amount: $7,269,177
RFA: Environmental Lung Disease Center (National Jewish Medical and Research Center) (1998)
Research Category: Targeted Research
Description:
Objective:The overall objectives of this research project were to: (1) define the effect of winter air pollution, predominately particulates, on children with severe asthma; (2) determine the effect of diesel emissions and ozone in Denver on a murine model of allergen-induced airway hyperresponsiveness; and (3) define the direct effects of ozone on lung epithelial cells. The main clinical project was on children with severe asthma because we felt that they were a special susceptible population, and we wanted to study patients with pre-existing lung disease.
We chose asthma because of the known adverse effects of air pollution on asthmatic patients and because of a unique opportunity in Denver to study a group of asthmatic children in a controlled environment with an opportunity to monitor exposure, symptoms, physiologic function, and medication use. In addition, we have an extensive research program in asthma and in future years can determine the mechanisms whereby different pollutants affect the respiratory and immune systems and alter airway responsiveness. Because of the unique opportunity of having a school for children with severe asthma on our campus, we could compare exposure to the clinical status in a very knowledgeable and responsive patient population. We also could define misclassification of exposures by comparing community standards to those onsite and to personal monitors used by the children at home.
Denver has a special climate and elevation that is representative of other Rocky Mountain cities but is different from U.S. coastal cities. Because of the altitude, for any given amount of work there is increased minute ventilation, which means more exposure to air pollutants. Furthermore, for any given level of lung impairment caused by chronic obstructive lung disease, there is more hypoxemia and pulmonary hypertension in Denver. These conditions cannot be simulated at sea level. Hence, studies in Denver will complement similar studies at sea level, and studies of susceptible populations of patients in Denver may uncover adverse health effects that may not be apparent at sea level.
Detection, assessment, and treatment of adverse health effects caused by air pollution require an understanding of mechanism. National Jewish Medical and Research Center uniquely affords the opportunity of bringing new expertise to bear for determining the mechanism of the effects of air pollutants individually or in combination on the initiation or modulation of the pulmonary inflammatory response. The advent of murine genetics and the opportunity of creating transgenic and gene knockout mice provide an opportunity to investigate the mechanism of injury, inflammation, and host response to air pollutants. In mice, we also can investigate the interactions between air pollution, allergic responses, viral infections, pulmonary inflammation, and lung function.
The final area of focus was on the effect of ozone on pulmonary epithelial cells. This part of the proposal determined the lipid peroxides that were formed by exposure of pulmonary surfactant and epithelial cells to ozone. The surprising finding was the discovery of bioactive cholesterol epoxides. This was a new finding and a new potential therapeutic target for oxidative injury, especially that caused by ozone.
Summary/Accomplishments (Outputs/Outcomes):Dr. Gelfand’s project failed to show any enhancement of airway inflammation or airway hyperresponsiveness to diesel exhaust particles. They tried to reproduce published findings but failed to reproduce the findings on enhancement of airway inflammation with diesel particles. Their conclusion was that diesel particles were poor inducers of airway inflammation and airway hyperresponsiveness. This is similar to the finding of Dr. Mason that ambient air particles did not increase serum pulmonary surfactant protein D. Hence, particles likely have a very low level of toxicity. This conclusion has been made by other researchers previously.
Dr. Gelfand’s studies with ozone were much more successful, although the dose used to induce a murine response in a small number of animals was above ambient levels of ozone. A 3-hour exposure of greater than 0.5 ppm produced a reproducible neutrophil influx, epithelial injury, and airway hyperresponsiveness. These effects were transient, however, and repair was seen at 24-48 hours. These acute effects were dependent on complement activation and were associated with an increase in IL-1β expression.
Dr. Rabinovitch sought to determine if winter air pollution, especially particulates, would worsen asthma in young severe asthma patients. Dr. Rabinovitch compared personal monitoring to local and central fixed monitors and showed that central monitors consistently overestimate personal exposures. Importantly, there also were higher levels of particulate exposures in homes in which there was cigarette smoking than central monitors. Hence, central monitors are relatively poor surrogates for individual person exposures. Use of personal monitors gave a much better indication of exposure as a result of particulates than central monitors. Dr. Rabinovitch also found that there was an association of immediate medication use and particulate concentrations. Hourly measurements, however, were necessary to establish this finding. There was no consistent effect of 24-hour averaged concentrations of particulates and asthma symptoms, medication use, or physiology in this cohort. Dr. Rabinovitch went on to show that urinary leukotriene E4 (LTE4) levels correlated with peak morning fine particulate matter (PM2.5) concentrations.
Dr. White showed that there was a rapid secretion of ATP upon exposure to low levels of ozone in vitro. This process was shown to be caused by vesicular transport. This ATP was a survival signal for epithelial cells. The implication is that stimulation of this pathway or exogenous ATP might mitigate against the effects of ozone. Dr. White and Dr. Murphy showed that oxidation of surfactant or epithelial cells produced biologically active cholesterol epoxides as well as an aldehyde derivative of phosphidylcholine. They went on to show that the oxidized lipid products also were formed in vivo after ozone exposure and could be recovered in lavage. The cholesterol epoxides are a new mediator likely to be responsible, in part, for the lung damage caused by ozone.
Dr. Mason showed that type II cells were much more sensitive than type I cells to ozone and from gene profiling data suggested that this might be related to glutaredoxin expression in type II cells. In both phenotypes that was induction of heat shock protein 70, hemoxygenase, and metallothionein. Neither cell type showed much of a chemokine response at the protein level. In both phenotypes there was increased secretion of chemokines in response to lipopolysaccharide (LPS) or IL-1β, but this effect was not altered by ozone. Preliminary data suggest that the known chemokine response is a result of cell-cell crosstalk with cell injury of a target cell, release of IL-1α, and subsequent secretion of chemokines by neighboring cells.
Conclusions
Ambient particulate exposure of moderately severe asthmatics in Denver does not markedly alter their symptoms, use of medicines, or pulmonary function. Personal monitors or hourly particulate measurements, however, show an effect of a decrease in forced expiratory volume with increasing particulate exposure. There was an increase in inhaled medication use with hourly PM2.5 levels but not with 24-hour averages. Urinary LTE4 levels correlated with morning particulate levels but not with 24-hour levels. Hence, monitoring should include personal monitors as well as rapid response hourly monitors were needed to show any associations with particulate levels in this cohort of severe asthmatic patients.
Ozone produced lipid peroxides in surfactant and in epithelial cells. These peroxides are toxic and may be responsible for the lung damage caused by ozone. Vesicular ATP release after ozone may protect the lungs from injury and is a survival signal. Epithelial cells don’t secrete much chemokine after exposure to ozone and there is no synergy with LPS or IL-1β. There likely is crosstalk, however, between ozone-damaged cells that send a signal (possibly IL-1α) to neighboring cells that, in turn, can produce chemokines.
Journal Articles: 39 Displayed | Download in RIS Format
| Other center views: | All 69 publications | 39 publications in selected types | All 39 journal articles |
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Ahmad S, Ahmad A, McConville G, Schneider BK, Allen CB, Manzer R, Mason RJ, White CW. Lung epithelial cells release ATP during ozone exposure: signaling for cell survival. Free Radical Biology and Medicine 2005;39(2):213-226. |
R825702C014 (Final) |
not available |
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Ahmad S, Ahmad A, McConville G, Schneider BK, Allen CB, Manzer R, Mason RJ, White CW. Lung epithelial cells release ATP during ozone exposure: signaling for cell survival. Free Radical Biology and Medicine 2005;39(2):213-226. |
R825702 (Final) |
not available |
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Allen MJ, Harbeck R, Smith B, Voelker DR, Mason RJ. Binding of rat and human surfactant proteins A and D to Aspergillus fumigatus conidia. Infection and Immunity 1999;67(9):4563-4569. |
R825702 (Final) R825702C001 (Final) |
not available |
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Allen MJ, Voelker DR, Mason RJ. Interactions of surfactant proteins A and D with Saccharomyces cerevisiae and Aspergillus fumigatus. Infection and Immunity 2001;69(4):2037-2044. |
R825702 (Final) R825702C001 (Final) |
not available |
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Allen MJ, Laederach A, Reilly PJ, Mason RJ. Polysaccharide recognition by surfactant protein D: novel interactions of a C-type lectin with nonterminal glucosyl residues. Biochemistry 2001;40(26):7789-7798. |
R825702 (Final) R825702C001 (Final) |
not available |
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Allen MJ, Laederach A, Reilly PJ, Mason RJ, Voelker DR. Arg343 in human surfactant protein D governs discrimination between glucose and N-acetylglucosamine ligands. Glycobiology 2004;14(8):693-700. |
R825702 (Final) R825702C001 (Final) |
not available |
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Cui Z-H, Joetham A, Aydintug MK, Hahn YS, Born WK, Gelfand EW. Reversal of allergic airway hyperreactivity after long-term allergen challenge depends on gammadelta T cells. American Journal of Respiratory and Critical Care Medicine 2003;168(11):1324-1332. |
R825702 (Final) R825702C012 (Final) |
not available |
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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-beta 1 in airway epithelial cells by Mycoplasma pneumoniae. American Journal of Respiratory Cell and Molecular Biology 2003;29(3 Pt 1):344-351. |
R825702 (Final) R825702C012 (Final) |
not available |
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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. |
R825702 (Final) R825702C012 (Final) |
not available |
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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 Pt 1):952-960. |
R825702 (Final) R825702C012 (Final) |
not available |
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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 Pt 1):1132-1139. |
R825702 (Final) R825702C012 (Final) |
not available |
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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. |
R825702 (Final) R825702C012 (Final) |
not available |
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Kanehiro A, Lahn M, Makela MJ, Dakhama A, Fujita M, Joetham A, Mason RJ, Born W, Gelfand EW. Tumor necrosis factor-alpha negatively regulates airway hyperresponsiveness through gamma-delta T cells. American Journal of Respiratory and Critical Care Medicine 2001;164(12):2229-2238. |
R825702 (Final) R825702C001 (Final) |
not available |
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Kanehiro A, Lahn M, Makela MJ, Dakhama A, Joetham A, Rha YH, Born W, Gelfand EW. Requirement for the p75 TNF-alpha receptor 2 in the regulation of airway hyperresponsiveness by gamma delta T cells. Journal of Immunology 2003;169(8):4190-4197. |
R825702 (Final) R825702C012 (Final) |
not available |
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Kumarathasan P, Blais E, Goegan P, Yagminas A, Guenette J, Adamson IY, Crapo JD, Mason RJ, Vincent R. 90-day repeated inhalation exposure of surfactant protein-C/tumor necrosis factor-alpha, (SP-C/TNF-alpha) transgenic mice to air pollutants. International Journal of Toxicology 2005;24(1):59-67. |
R825702 (Final) R825702C001 (Final) |
not available |
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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. |
R825702 (Final) R825702C012 (Final) |
not available |
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Manzer R, Wang J, Nishina K, McConville G, Mason RJ. Alveolar epithelial cells secrete chemokines in response to IL-1beta and lipopolysaccharide but not to ozone. American Journal of Respiratory Cell and Molecular Biology 2006;34(2):158-166. |
R825702 (Final) R825702C001 (Final) |
not available |
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Pan T, Nielsen LD, Allen MJ, Shannon KM, Shannon JM, Selman M, Mason RJ. Serum SP-D is a marker of lung injury in rats. American Journal of Physiology-Lung Cellular and Molecular Physiology 2002;282(4):L824-L832. |
R825702 (Final) R825702C001 (Final) |
not available |
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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. Journal of Allergy and Clinical Immunology 2003;112(6):1078-1087. |
R825702 (Final) R825702C012 (Final) |
not available |
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Park JW, Taube C, Joetham A, Takeda K, Kodama T, Dakhama A, McConville G, Allen CB, Sfyoera G, Schultz LD, Lambris JD, Giclas P, 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. |
R825702 (Final) R825702C012 (Final) |
not available |
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Park JW, Taube C, Swasey C, Kodama T, Joetham A, Balhorn A, Takeda K, Miyahara N, Allen CB, Dakhama A, Kim SH, 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. |
R825702 (Final) R825702C012 (Final) |
not available |
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Pulfer MK, Taube C, Gelfand E, Murphy RC. Ozone exposure in vivo and formation of biologically active oxysterols in the lung. Journal of Pharmacology and Experimental Therapeutics 2005;312(1):256-264. |
R825702 (Final) R825702C014 (Final) |
not available |
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Rabinovitch N, Zhang L, Murphy JR, Vedal S, Dutton SJ, Gelfand EW. Effects of wintertime ambient air pollutants on asthma exacerbations in urban minority children with moderate to severe disease. Journal of Allergy and Clinical Immunology 2004;114(5):1131-1137. |
R825702 (Final) R825702C013 (Final) |
not available |
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Rabinovitch N, Liu AH, Zhang L, Rodes CE, Foarde K, Dutton SJ, Murphy JR, Gelfand EW. Importance of the personal endotoxin cloud in school-age children with asthma. Journal of Allergy and Clinical Immunology 2005;116(5):1053-1057. |
R825702 (Final) R825702C013 (Final) |
not available |
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Rabinovitch N, Liu AH, Zhang L, Foarde K, Rodes CE, Gelfand EW. Increased respirable endotoxin exposure with furry pets. Allergy 2006;61(5):650-651. |
R825702 (Final) R825702C013 (Final) |
not available |
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Rabinovitch N, Strand M, Gelfand EW. Particulate levels are associated with early asthma worsening in children with persistent disease. American Journal of Respiratory and Critical Care Medicine 2006;173(10):1098-1105. |
R825702 (Final) R825702C013 (Final) |
not available |
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Rha Y-H, Taube C, Haczku A, Joetham A, Takeda K, Duez C, Siegel M, Aydintug MK, Born W, Dakhama A, Gelfand EW. Effect of microbial heat shock proteins on airway inflammation and hyperresponsiveness. Journal of Immunology 2002;169(9):5300-5307. |
R825702 (Final) R825702C012 (Final) |
not available |
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Strand M, Vedal S, Rodes C, Dutton SJ, Gelfand EW, Rabinovitch N. Estimating effects of ambient PM2.5 exposure on health using PM2.5 component measurements and regression calibration. Journal of Exposure Science & Environmental Epidemiology 2006;16(5):471. |
R825702 (Final) R825702C013 (Final) |
not available |
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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. |
R825702 (Final) R825702C012 (Final) |
not available |
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Taylor MD, Van Dyke K, Bowman LL, Miles PR, Hubbs AF, Mason RJ, Shannon K, Reasor MJ. A characterization of amiodarone-induced pulmonary toxicity in F344 rats and identification of surfactant protein-D as a potential biomarker for the development of the toxicity. Toxicology and Applied Pharmacology 2000;167(3):182-190. |
R825702 (Final) R825702C001 (Final) |
not available |
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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. |
R825702 (Final) R825702C012 (Final) |
not available |
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Zhang F, Pao W, Umphress SM, Jakowlew SB, Meyer AM, Dwyer-Nield LD, Nielsen LD, Takeda K, Gelfand EW, Fisher JH, Zhang L, Malkinson AM, Mason RJ. Serum levels of surfactant protein D are increased in mice with lung tumors. Cancer Research 2003;63(18):5889-5894. |
R825702 (Final) R825702C001 (Final) |
not available |
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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. |
R825702 (Final) R825702C012 (Final) |
not available |
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Larsen GL, White CW, Takeda K, Loader JE, Nguyen DD, 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. |
R825702 (Final) R825702C012 (Final) |
not available |
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Uhlson C, Harrison K, Allen CB, Ahmad S, White CW, Murphy RC. Oxidized phospholipids derived from ozone-treated lung surfactant extract reduce macrophage and epithelial cell viability. Chemical Research in Toxicology 2002;15(7):896-906. |
R825702 (Final) R825702C014 (Final) |
not available |
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Makela MJ, Tripp R, Dakhama A, Park JW, Ikemura T, Joetham A, Waris M, Anderson LJ, Gelfand EW. Prior airway exposure to allergen enhances virus-induced airway hyperresponsiveness. Journal of Allergy and Clinical Immunology 2003;112(5):861-869. |
R825702 (Final) R825702C012 (Final) |
not available |
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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. |
R825702 (Final) R825702C012 (Final) |
not available |
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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. |
R825702 (Final) R825702C012 (Final) |
not available |
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Taube C, Nick JA, Siegmund B, Duez C, Takeda K, Rha Y-H, Park JW, 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 Molecular Biology 2004;30(6):837-843. |
R825702 (Final) R825702C012 (Final) |
not available |
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,
,
Air, Scientific Discipline, Health, Biology, Risk Assessments, Disease & Cumulative Effects, Health Risk Assessment, Epidemiology, air toxics, Atmospheric Sciences, Biochemistry, health effects, environmental toxicant, human health risk, susceptibility, genetic susceptibility, air pollutants, occupational exposure, acute lung injury, airway disease, lung disease, lung epithelial cells, human exposure, animal studies
Relevant Websites:
http://www.nationaljewish.org/patient-info/progs/med/environmental/index.aspx 
Progress and Final Reports:
Original Abstract
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