2014 Progress Report: Environmental Determinants of Host Defense

EPA Grant Number: RD834515C003
Subproject: this is subproject number 003 , established and managed by the Center Director under grant RD834515
(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: Environmental Determinants of Host Defense
Investigators: Schwartz, David A.
Current Investigators: Schwartz, David A. , Yang, Ivana , Huber, Jonathan , Oakes, Judy , Eyring, Ken
Institution: National Jewish Health
Current Institution: National Jewish Health , University of Colorado at Denver
EPA Project Officer: Hahn, Intaek
Project Period: September 1, 2009 through August 31, 2014 (Extended to June 21, 2017)
Project Period Covered by this Report: September 1, 2013 through August 31,2014
RFA: Children's Environmental Health and Disease Prevention Research Centers (with NIEHS) (2009) RFA Text |  Recipients Lists
Research Category: Children's Health , Health

Objective:

The overall goal of this project is to understand how and why air pollution alters lung host defense. While the proposed research is focused on mice, we believe that the discoveries we make in mice will prove to be relevant to basic mechanisms of lung host defense in children. In fact, our findings in mice will be tested in Project 1 of this program. The environmental, clinical, and biological significance of this project is supported by the following observations. First, air pollution accounts for substantial morbidity and mortality throughout the world, including lung infections and preventable deaths in children. Second, endotoxin is ubiquitous in the environment and is associated with the development and progression of asthma and other forms of airway disease. However, the relationship between endotoxin and asthma is not simple because early childhood exposure to endotoxin, at least in certain populations, appears to protect children from developing asthma and atopy. Air pollution is contaminated with endotoxin, so this pathogen associated molecular pattern (PAMP) or other PAMPs may play a role in the pathophysiology of air pollution. Third, the ability of the host to respond to lipopolysaccharide (LPS; a specific form of endotoxin) and other PAMPs is highly variable in mice and humans, yet polymorphic host defense genes only account for a portion of this variable response. Fourth, innate immunity provides a first line of host defense against microbial pathogens that is conserved over a wide variety of species from flies to mammals. Indeed, innate immune signaling mechanisms in mice are almost identical to those in humans. Finally, the innate immune system is biologically dynamic and is responsive to both ozone and PAMPs. We recently have found that the expression of innate immune receptors on macrophages can be enhanced by ozone or PAMPs. Moreover, others have reported that some innate immune cells avoid excessive inflammation by selectively downregulating proinflammatory genes while continuing to transcribe antimicrobial genes. Thus, the overall hypothesis of this project is that the expression of toll-­like receptors (TLRs) in the lung is influenced by environmental (ozone and/or PAMPs) and genetic factors, and the dynamic expression of TLRs has profound effects on lung host defense and, consequently, the development of lung infections and allergic airway disease.

Progress Summary:

We completed characterization of the effect of in vivo ozone exposure on lung innate immune response to Pam3CYS, a TLR2/TLR6 agonist. Ozone pre-exposure resulted in (1) increased whole lung lavage (WLL) cell influx; (2) increased IL-6 and KC, and decreased MIP-1α and TNF-α; and (3) increased cell surface expression of TLR4, TLR2 and TLR1 on macrophages as a result of ozone alone or in combination with Pam3CYS. In addition, we demonstrated that ozone followed by Pam3CYS resulted in a large increase in phosphorylation of both p44/42 (Erk1/2) MAPK and JNK kinases and significant reduction in non-phosphorylated p44/42 MAPK at 4 hours post Pam3CYS. This enhanced signal associated with ozone/Pam3CYS treatment was not present at 24 hours. To further characterize the priming effect of ozone on innate immunity at the molecular level in an unbiased manner, we performed gene expression profiling on lung tissue of mice from the four exposure groups. Ozone exposure has the strongest effect on gene expression at the 4-hour time point with the effect diminishing by the 24-hour time point. Ozone pre-exposure prior to Pam3CYS treatment (O3/Pam3CYS vs. FA/Pam3CYS) enhanced induction of Trmt5 at the 4 hours and Cck at 24 hours. Expression of Ttk (4-hour time point), Pbp2, Gjb4, Ncapg, and Pbk (24-hour time point) also were increased in the O3/Pam3CYS vs. FA/Pam3CYS but significantly less than in the O3/saline vs. FA/saline comparison. The most significant result among downregulated genes is downregulation at 24 hours of killer cell lectin-like receptors (Klra3, Klra8, Klra9, Klra10, Klra15, Klra21, Klra22, Klra23, Klrb1a, and Klrk1). Our study demonstrates that expression of TLRs on macrophage surface is a dynamic process that is influenced by ozone and that this process is associated with differential expression of a number of previously unexplored genes. This dynamic nature of TLR expression is likely more general and could be influenced by other components of air pollution and in cell types other than macrophages. This priming effect of air pollution and genes that are associated with the process also represent potential therapeutic targets for air pollutant exposure in the context of pulmonary infection or allergic airway inflammation.

To understand how epigenetic mechanisms alter dendritic cell function and contribute to the etiology of allergic airway disease, we are developing a line of investigation that examines epigenetic marks and transcriptional profiles in distinct lineages of DCs that exist within the lung and are recruited to the draining lymph nodes in response to allergic sensitization. Preliminary data demonstrate the approach we are taking to isolating these cells for epigenetic and gene expression studies.

To follow up on our published findings on the role of methyl donor diet in the development of allergic airway disease in mice, we compared allergic airway disease phenotypes between methylene-tetrahydrofolate reductase (MTHFR) deficient mice on a C57/Bl6 background to wild-type (WT) C57/Bl6 mice using a house dust mite (HDM) allergen model. In brief, mice received an intraperitoneal (i.p.) sensitization of 10 μg HDM or saline on days 0 and 7 followed by an intratracheal (i.t.) challenge of 5 μg HDM or saline on days 14 and 15. Forty-eight hours after the final challenge, total cells and eosinophils in the bronchoalveolar lavage were 5.76 fold and 7.87 lower, respectively, in HDM-treated MTHFR deficient compared to HDM-treated WT mice. Furthermore, HDM-treated MTHFR KO mice demonstrate a 1.64 fold (p < 0.05) reduction in lung resistance compared to HDM-treated WT mice in response to inhaled methacholine. These results suggest that allergic airway disease may be suppressed through the loss of MTHFR.

During the fifth year of this project on environmental asthma, substantial progress has taken place. All three independent projects and the three Cores have made excellent progress and have met all of their goals. The overall structure and necessary interactions within the Program is established, productive, and is insuring the continued success of the Program. Center investigators meet at least every month and scientific discussions and scientific collaborations between the investigators are naturally evolving. We are actively engaged in considering scientific options for our competitive renewal.

Future Activities:

The coming year will include continuation of DAPS visits, analyses and preparation of our findings for presentation and manuscript submissions. Findings from our DAPS‐EPEM preliminary analyses were selected for presentation at the 2015 American Academy of Allergy, Asthma & Immunology Annual Meeting (Best of Environmental and Occupational Respiratory Diseases Interest Section) and the 2015 American Thoracic Society International Conference, and are being developed for publication. For the NIH‐funded CAMP study, the Endotoxin Exposure Working Group completed its analyses, presented this work at the 2014 American Academy of Allergy, Asthma & Immunology Annual Meeting (Best of Environmental and Occupational Respiratory Diseases Interest Section), and is in the final stages of manuscript preparation for submission of their findings. We completed our collaborative investigation of endotoxin exposure and asthma outcomes in 150 inner-city children in Baltimore (NIH-funded MAACS Study: PI E. Matsui) and a manuscript of our findings was published. We also completed a collaborative investigation of endotoxin exposure and early childhood wheezing phenotypes in a Denver inner city pre-school cohort (NIH-funded CAPS Study). This was presented in 2014 at a premier meeting, and it is in the final stages of manuscript preparation for submission. What we have learned from our CAMP, EPEM, MAACS, HUD and CAPS studies, and the other Projects and COTC in our CEHC, has informed and strengthened DAPS.


Journal Articles on this Report : 14 Displayed | Download in RIS Format

Other subproject views: All 23 publications 14 publications in selected types All 14 journal articles
Other center views: All 51 publications 30 publications in selected types All 30 journal articles
Type Citation Sub Project Document Sources
Journal Article Das R, Subrahmanyan L, Yang IV, van Duin D, Levy R, Piecychna M, Leng L, Montgomery RR, Shaw A, Schwartz DA, Bucala R. Functional polymorphisms in the gene encoding macrophage migration inhibitory factor are associated with gram-negative bacteremia in older adults. Journal of Infectious Diseases 2014;209(5):764-768. RD834515 (2013)
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  • Journal Article De Arras L, Seng A, Lackford B, Keikhaee MR, Bowerman B, Freedman JH, Schwartz DA, Alper S. An evolutionarily conserved innate immunity protein interaction network. Journal of Biological Chemistry 2013;288(3):1967-1978. RD834515 (2013)
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  • Journal Article Gabehart K, Correll KA, Yang J, Collins ML, Loader JE, Leach S, White CW, Dakhama A. Transcriptome profiling of the newborn mouse lung response to acute ozone exposure. Toxicological Sciences 2014;138(1):175-190. RD834515 (2011)
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  • Journal Article Gabehart K, Correll KA, Loader JE, White CW, Dakhama A. The lung response to ozone is determined by age and is partially dependent on toll-like receptor 4. Respiratory Research 2015;16:117. RD834515 (2013)
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  • Journal Article Gao Z, Dosman JA, Rennie DC, Schwartz DA, Yang IV, Beach J, Senthilselvan A. NOS3 polymorphism, lung function, and exposure in swine operations: results of 2 studies. Journal of Allergy and Clinical Immunology 2014;134(2):485-488. RD834515 (2013)
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  • Journal Article Henao-Martinez AF, Agler AH, LaFlamme D, Schwartz DA, Yang IV. Polymorphisms in the SUFU gene are associated with organ injury protection and sepsis severity in patients with Enterobacteriacea bacteremia. Infection, Genetics and Evolution 2013;16:386-391. RD834515 (2013)
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  • Journal Article Jing J, Yang IV, Hui L, Patel JA, Evans CM, Prikeris R, Kobzik L, O'Connor BP, Schwartz DA. Role of macrophage receptor with collagenous structure in innate immune tolerance. Journal of Immunology 2013;190(12):6360-6367. RD834515 (2013)
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  • Journal Article Kelada SN, Wilson MS, Tavarez U, Kubalanza K, Borate B, Whitehead GS, Maruoka S, Roy MG, Olive M, Carpenter DE, Brass DM, Wynn TA, Cook DN, Evans CM, Schwartz DA, Collins FS. Strain-dependent genomic factors affect allergen-induced airway hyperresponsiveness in mice. American Journal of Respiratory Cell and Molecular Biology 2011;45(4):817-824. RD834515 (2013)
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  • Journal Article Lai PS, Hofmann O, Baron RM, Cernadas M, Meng QR, Bresler HS, Brass DM, Yang IV, Schwartz DA, Christiani DC, Hide W. Integrating murine gene expression studies to understand obstructive lung disease due to chronic inhaled endotoxin. PLoS One 2013;8(5):e62910. RD834515 (2013)
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  • Journal Article Long H, O'Connor BP, Zemans RL, Zhou X, Yang IV, Schwartz DA. The Toll-like receptor 4 polymorphism Asp299Gly but not Thr399Ile influences TLR4 signaling and function. PLoS One 2014;9(4):e93550 (10 pp.). RD834515 (2013)
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  • Journal Article Matsui EC, Hansel NN, Aloe C, Schiltz AM, Peng RD, Rabinovitch N, Ong MJ, Williams DL, Breysse PN, Diette GB, Liu AH. Indoor pollutant exposures modify the effect of airborne endotoxin on asthma in urban children. American Journal of Respiratory and Critical Care Medicine 2013;188(10):1210-1215. RD834515 (2012)
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  • Journal Article Oakes JL, O'Connor BP, Warg LA, Burton R, Hock A, Loader J, LaFlamme D, Jing J, Hui L, Schwartz DA, Yang IV. Ozone enhances pulmonary innate immune response to a Toll-like receptor-2 agonist. American Journal of Respiratory Cell and Molecular Biology 2013;48(1):27-34. RD834515 (2013)
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  • Journal Article Warg LA, Oakes JL, Burton R, Neidermyer AJ, Rutledge HR, Groshong S, Schwartz DA, Yang IV. The role of the E2F1 transcription factor in the innate immune response to systemic LPS. American Journal of Physiology-Lung Cellular and Molecular Physiology 2012;303(5):L391-L400. RD834515 (2013)
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  • Journal Article Yang IV, Alper S, Lackford B, Rutledge H, Warg LA, Burch LH, Schwartz DA. Novel regulators of the systemic response to lipopolysaccharide. American Journal of Respiratory Cell and Molecular Biology 2011;45(2):393-402. RD834515 (2013)
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  • Supplemental Keywords:

    Endotoxin, exposure, children, asthma, risk, health effects, susceptibility, sensitive populations, genetic pre-disposition, genetic polymorphism, indoor air, dose-response, ozone, remediation, asthma indices, intervention, asthma triggers, allergic response, airway inflammation, Health, Scientific Discipline, HUMAN HEALTH, Health Risk Assessment, Allergens/Asthma, Health Effects, Biology, asthma, sensitive populations, asthma triggers, endotoxin, children, airway inflammation, allergic response

    Progress and Final Reports:

    Original Abstract
  • 2010
  • 2011
  • 2012
  • 2013
  • 2015
  • 2016 Progress Report
  • Final

  • Main Center Abstract and Reports:

    RD834515    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).
    RD834515C001 Endotoxin Exposure and Asthma in Children
    RD834515C002 Environmental Determinants of Early Host Response to RSV
    RD834515C003 Environmental Determinants of Host Defense