2011 Progress Report: Endotoxin Exposure and Asthma in Children

EPA Grant Number: RD834515
Center: Denver Children’s Environmental Health Center - Environmental Determinants of Airway Disease in Children
Center Director: Schwartz, David A.
Title: Endotoxin Exposure and Asthma in Children
Investigators: Schwartz, David A. , Covar, Ronina A , Litonjua, Augusto A. , Liu, Andrew H. , Van Dyke, Michael V. , White, Carl W. , Forssen, Anna , Dakhama, Azzeddine , Yang, Ivana , Yang, Jing , Loader, Joan , Sordillo, Joanne , Oakes, Judy , Correll, Kelly , Gabehart, Kelsa , Rabinovitch, Nathan , Szefler, Stanley
Current Investigators: Schwartz, David A. , Covar, Ronina A , Litonjua, Augusto A. , Liu, Andrew H. , Murphy, Amy J , Strand, Mathew J. , Van Dyke, Michael V. , Martyny, John W. , Rabinovitch, Nathan
Institution: National Jewish Health
EPA Project Officer: Hahn, Intaek
Project Period: June 22, 2010 through June 21, 2015 (Extended to June 21, 2017)
Project Period Covered by this Report: June 22, 2011 through June 21,2012
Project Amount: $1,897,209
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 Center is conducting three research projects, each of which has a 2011 annual report. This overall report summarizes the Center projects and the activities of the Community Outreach and Translation Core (COTC).

Project 1: Endotoxin Exposure and Asthma in Children

We hypothesize that higher levels of endotoxin exposure cause persistent, problematic asthma and that key environmental (ozone and allergens) and genetic modifiers (endotoxin receptor polymorphisms) contribute to endotoxin susceptibility and pathological asthmatic responses. We are studying these endotoxin-induced airway conditions in children through three complementary clinical investigations.

First, we are capitalizing on an ancillary study of a NIH-sponsored multi center cohort of children with asthma (Childhood Asthma Management Program), which has tracked asthma severity for over a decade, to determine if endotoxin exposure, modified by genetics and environment, is associated with greater disease severity and persistence.

Second, we are planning a panel study of children with asthma to investigate whether endotoxin exposure, modified by environment, is associated with inflamed airways and elevated TLR expression on airway macrophages. Clinically, these inflammatory responses could drive poor asthma control and exacerbations.

Finally, we are taking advantage of a HUD-sponsored inner-city home intervention study to determine if a home environment intervention will reduce home endotoxin levels and improve asthma. This combination of studies are expected to provide an understanding of how endotoxin interacts with other potentially toxic exposures in the susceptible host to cause persistent, problematic asthma. These studies will help us to determine the levels of endotoxin exposure that are likely to be problematic for children with asthma, and to develop environmental educational and intervention programs to improve health outcomes.

Project 2: Environmental Determinants of Early Host Response to RSV

The pollutant ozone is suspected to play a significant role in the development and exacerbation of reactive airway diseases such as asthma. Ozone exposure may alter lung development and growth, especially in the early post-natal development phase, resulting in increased susceptibility to airway obstruction upon subsequent viral infection and allergen exposure. Ozone exposure can also influence the innate immune response by increasing Toll-like receptor (TLR)-4 expression, thereby increasing airway responsiveness to bacterial endotoxin (LPS). LPS is also known to mature dendritic cells, the primary immune cell subset that initiates T cell differentiation and directs the adaptive response. The overall hypothesis of this project is that ozone exposure, in the early postnatal phase, alters lung development and modifies the host immune response to early life viral infection and allergen exposure, thereby contributing to the development of reactive airway disease. In the presence of LPS, however, lung development will be sustained and the host immune response will mature and protect the newborn against the development of altered airway responses to viral infection and allergen exposure. Specific Aim 1: To define the influence of ozone exposure on TLR expression and airway structure and function. Specific Aim 2: To define the influence of ozone exposure on airway responsiveness to respiratory syncytial virus (RSV) and allergen. Specific Aim 3: To determine if and how LPS can modify airway responsiveness to RSV infection and allergen, following postnatal exposure to ozone.

Project 3: Environmental Determinants of Host Defense

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 since 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 have recently 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 are 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.

COTC

Our CAB’s priority is to target youth by integrating air quality and health into the state’s curriculum. The overall goal is to prepare Colorado youth to become critical thinkers capable of making informed decisions and taking actions to improve their environment and health. As identified last year, two of our objectives were to: (1) develop and disseminate a resource that compiles and reviews existing lesson plans and resources for integrating lung health, environmental health, and critical thinking into the curricula of grades K-12 and (2) identify models for integrating lung health, environmental health and critical thinking into the curricula of grades K-12. These objectives were accomplished. To assist educators, a resource of “best” lesson plans and supports was developed that followed a formal review and assessment process. Twenty-one programs consisting of 192 resources underwent a second level review against pre-identified criteria to identify “best” resources. Following this review, 17 lesson plans were identified as ready to use, 39 needed additional work and 136 were not useful. A website (www.capk-12.org) was created to make these resources available as a one-stop source for educators.

Progress Summary:

Project 1: Endotoxin Exposure and Asthma in Children

As proposed, three complementary studies address the aims and hypotheses of Project 1: (1) Childhood Asthma Management Program (CAMP) ancillary study; (2) Denver Panel Study (DPS); and (3) Housing & Urban Development (HUD) ancillary study. The lab measure of endotoxin has been based on an assay reagent (Limulus amebocyte lysate) that measures both endotoxin and molds. Recently, a newly developed endotoxin assay based on a recombinant endotoxin receptor (Factor C) specifically measures endotoxin. To advance scientific understanding of pure endotoxin exposure (i.e., independent of mold) and asthma outcomes, during the past year, we developed and validated a Standard Operating Procedure to measure endotoxin using Recombinant Factor C, and established quality control parameters.

  1. For the CAMP study, endotoxin levels were measured on house dust samples from 962 CAMP study participants obtained at enrollment, and we are analyzing the relationship of endotoxin levels with asthma severity, airway obstruction and hyper-responsiveness, asthma persistence, and exacerbations. The CAMP study also collected home mold counts at enrollment. Since molds, like endotoxin, are microbial exposures, we are analyzing the relationship of CAMP mold levels with asthma outcomes. This will help us better understand the independent contributions of endotoxin and mold exposures on asthma outcomes.

    In the CAMP study, we are also analyzing the relationship of home endotoxin and mold levels with CAMP measures of allergy and inflammation associated with asthma (blood eosinophils, serum IgE, allergic sensitization) that were obtained at enrollment. In the CAMP study, we are currently analyzing the interaction of home endotoxin and mold levels with home allergy (i.e., allergic sensitization and high levels of exposure) on asthma outcomes. Home allergen exposure and dust allergen levels have been determined in CAMP. We have also investigated the interaction of endotoxin with 48 SNPs in 11 Toll-Like Receptor (TLR) genes (TLR-1, -2, -3, -4, -5, -6, -9, -10, CD14, MyD88, LY96, ACAA1) on severe asthma exacerbations (i.e., at least one ER visit or hospitalization for asthma in the past year). This preliminary analysis was restricted to CAMP participants of Caucasian ethnicity: 517 CAMP Caucasian participants included 84 cases with at least one severe asthma exacerbation vs. 433 controls. For two SNPs (in TLR9 and MyD88), the presence of the dominant genotype and higher endotoxin levels increase the risk of severe asthma exacerbations. Because of these significant TLR gene-endotoxin interactions, we have expanded our genotyping of genes downstream of the TLR receptor complex.
  2. For the DPS Study, we are planning a longitudinal study of children with asthma, to investigate airways inflammation, immunity, and TLR expression associated with endotoxin and ozone exposure. We expect to determine if these exposures prime the airways for aberrant responses to respiratory viruses, leading to fall seasonal exacerbations. Relevant findings from our other Project 1 studies and our other Denver CEHC Projects will be considered when developing this investigation in order to incorporate the most contemporary perspectives and hypotheses into this investigation.

    For the HUD study, 115 participants were enrolled, and the study participant follow-up visits were completed in March 2012. The HUD cohort was comprised of mostly ethnic minority children with asthma living in low-income housing. Their homes had many asthma triggers that were targets for remediation at 3 levels: Education Only, Minor Remediation, and Moderate Remediation. We are currently analyzing dust samples for endotoxin concentrations. In preliminary analyses, house dust endotoxin levels from the bedroom and general living areas of 60 homes differed between the homes characterized as needing Education only (lowest levels), Minor Remediation, or Moderate Remediation (highest levels). All families received an educational intervention consisting of results from their home environmental assessment and tailored educational materials and remediation recommendations based on these results, such as EPA’s publications: Clear Your Home of Asthma Triggers; A Brief Guide to Mold, Moisture, and Your Home; and Protect Your Family and Yourself from Carbon Monoxide. All families with a smoker living in the house received guidance on establishing a smoke-free home and referral to the Colorado QuitLine, a free phone-based smoking cessation program.

Project 2: Environmental Determinants of Early Host Response to RSV

This project has made substantial progress in achieving its overall objective to characterize the influence of postnatal ozone exposure on TLR expression and on airway structure and function. The data accumulated so far in Aim 1 are being drafted into 2 manuscripts, currently under preparation. In addition to transcriptome (mRNA expression) analyses, we also carried out microRNA (miR) expression analyses of infant mouse lungs to identify key miRs involved in regulating the lung mRNA response to acute postnatal ozone exposure. Studies of airway responses to acute ozone exposure revealed some important age-related differences. In infant mice, compared to adolescent/adult mice, ozone exposure induced limited airway tissue damage (lung permeability, airway neutrophilic inflammation) but increased airway mucus production and neurogenic activity. As the lung developed, neutrophilic inflammation, lung permeability and anti-oxidant responses increased. It is not clear yet if and how the infant mouse lung is protected against ozone but it seems plausible that their elevated mucus production might contribute to this protection. We are exploring a potential mechanism for this mucus production, which appears to be independent of IL-13, a known master regulator of mucus hyperproduction in allergic airway disease. In addition, our recent analyses of lung structure, using advanced stereology techniques, indicated that a single (acute) ozone exposure did not alter lung volume or numbers of alveoli in exposed infant mice. Thus, although a single ozone exposure appeared to negatively impact cell cycle-related mRNA expression pathways as clearly indicated in our transcriptome analysis, such an effect might be only transient and insufficient to translate into structural changes. Significant progress has been made in Aim 2. The results obtained recently have been communicated this year in the form of abstract presentations to the AAAAI and ATS 2012 international conferences. Studies of the effects of acute ozone on subsequent airway sensitization to allergen and development of allergic airway disease indicated that postnatal ozone activated dendritic cells and increased allergen-induced airway hyperresponsiveness (AHR) but not airway inflammation or Th2 cytokine production. The mechanism underlying this enhancement of allergen-induced AHR does not seem to be via increased allergic sensitization or airway inflammation, and further studies will determine if it is mediated through a neurogenic mechanism. Studies examining the effect of postnatal ozone (both acute and repeated exposures) on airway response to respiratory syncytial virus have just begun. These studies will determine if the innate and adaptive immune airway responses to the virus are altered and lead to severe infection and disease.

Project 3: Environmental Determinants of Host Defense

During the past year, we focused on characterizing the effect of in vivo ozone exposure on lung innate immune responses to Pam3CYS, a TLR2/TLR6 agonist. Mice were exposed to either ozone or filtered air (FA). Following ozone exposure, mice from either the ozone or FA group were treated intratracheally with either Pam3CYS in saline or saline alone. Cells and cytokines in the whole-lung lavage, surface expression of TLRs on macrophages, and lung RNA genomic expression profiles were examined. Potentially novel ozone priming genes were identified. Our results extend previous findings with ozone/LPS to other PAMPs and suggest that ozone priming of innate immunity is a general mechanism. Gene expression profiling of lung tissue identified transcriptional networks and genes that contribute to the priming of innate immunity at the molecular level. We also have implemented a house dust mite (HDM) model of allergic airway disease in which 6-8 week old male mice are sensitized by administration of whole HDM extract in sterile saline intraperitonially (i.p.). Following i.p. sensitization, mice are challenged by intratracheal instillation of HDM. Subsequently, mice are anesthetized for AHR assessment followed by BAL and lung tissue harvest.

COTC

COTC staff and CEHC investigators provided presentations to several community workshops/seminars with attendees from across Colorado and EPA Region 8 and to several school classrooms to support environmental literacy, critical thinking, policy review and development, and the translation of research/evidence into action. COTC staff worked with the San Luis Valley Ecosystem Council to submit a grant request to the EPA for funding of programs and activities to improve indoor air quality and reduce respiratory-related burden.

COTC Co-Directors (Lisa Cicutto and Stan Szefler), COTC staff (Melanie Gleason) and CEHC Investigator (Andy Liu) attended the EPA’s and NIEHS’ Children’s Environmental Health Center and Partnerships for Environmental Public Health meetings in March 2012. Dr. Szefler presented on the topic of “Personalizing Asthma Therapy: Assessing the Environment.” Poster presentations were also made at these conferences to highlight our website of “best available” resources for improving environmental literacy and critical thinking for K-12 students.

The COTC was also successful in attaining an EPA Environmental Education Award for $150,000 that will allow the COTC to work with multiple community partners to improve the uptake of environmental education initiatives provided to youth. Through this EPA award, at least 19 sub-awards will be made to community partners working with youth to prepare our next generation of environmental stewards related to air quality and health.

COTC staff worked with the San Luis Valley Ecosystem Council to submit a grant request to the EPA for a CARE Indoor Air Quality Project. The application was successful. The COTC will be partnering with a variety of community organizations to prepare informational materials for the lay public and professionals and will also be performing workforce trainings and continuing professional education. Region 8 EPA staff were instrumental in “connecting” the COTC staff with the San Luis Valley Ecosystem Council.

Future Activities:

Project 1: Endotoxin Exposure and Asthma in Children

The coming year will be an active period of analyses and preparation of our findings for presentation and manuscript submissions. For the CAMP study, two working groups, endotoxin exposure and TLR genetics groups, are anticipating completion of their analyses and manuscripts of their findings for submission in 3–6 months and 4–9 months, respectively. The HUD study analyses will be completed in the next 3 months. What we learn from the CAMP and HUD studies, and the other Projects and COTC in our CEHC, will help inform the development of our DPS longitudinal study planned for Years 3–5 of this award.

We are considering collaboration in an ancillary study of endotoxin exposure and asthma outcomes in 150 inner city children in Baltimore (MAACS Study: PI E. Matsui). Participants with at-risk asthma and mouse infestation of their homes were enrolled in this one-year longitudinal study. Air filter and house dust samples are available for endotoxin measurement at 5 different time points over the course of the year. This collaboration would complement and potentially validate the findings in our proposed studies addressing Aims 1, 2, and 3:

  • Aim 1: to determine if endotoxin exposure in children with asthma is associated with greater disease severity, manifesting as chronic airways obstruction, exacerbations, bronchial hyperresponsiveness (BHR), and persistent disease;
  • Aim 2: to determine if endotoxin exposure in children with asthma is associated with inflamed airways and elevated TLR expression on airway macrophages.
  • Aim 3: to determine if endotoxin-induced airways obstruction, inflammation, and exacerbations will be worsened by environmental exposures indoor allergic sensitization with relevant allergen exposure.

In preliminary work, our endotoxin rFC methodology is sensitive and specific enough to measure low- to moderate levels of endotoxin collected on air filter samples provided by MAACS investigators. This study could be the first investigation of airborne endotoxin using the more specific Recombinant Factor C assay.

Project 2: Environmental Determinants of Early Host Response to RSV

Complete Aim 2 by the end of 2012 and publish the results. Initiate Aim 3 studies in the Fall of 2012.

Project 3: Environmental Determinants of Host Defense

Determine the effect of in vitro exposures to ozone and/or PAMPs on the expression of TLRs in murine macrophages and dendritic cells. Determine the effect of in vivo exposures to ozone and/or PAMPs on the expression of TLRs in mouse lungs. Determine the effect of in vivo exposures to ozone and/or PAMPs on susceptibility of mice to lung pathogens. Determine the effect of in vivo exposures to ozone and/or PAMPs on HDM sensitization and the development of HDM induced allergic airway disease in mice.

COTC

The COTC's plans for the next year are to:

  1. Identify and refine models for integrating lung health, environmental health and critical thinking into the curricula of grades K-12;
  2. Work with Aurora Public Schools to develop a middle school curriculum that integrates lung and environmental health into an inquiry-based framework;
  3. Develop a framework for evaluating the effectiveness of models to improve both the integration of environment and lung health in K-12 schools and students’ awareness, understanding and self-efficacy as a result of the information covered; and
  4. Develop and disseminate educational resources on particulate matter, pesticides, endotoxin, and ozone for the general public and those affected by breathing problems.

In addition, CAB members and CEHC investigators will work together to translate and disseminate the results of CEHC studies to community members.


Journal Articles: 31 Displayed | Download in RIS Format

Other center views: All 51 publications 30 publications in selected types All 30 journal articles
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Journal Article Alper S, Warg LA, De Arras L, Flatley BR, Davidson EJ, Adams J, Smith K, Wohlford-Lenane CL, McCray Jr PB, Pedersen BS, Schwartz DA, Yang IV. Novel Innate Immune Genes Regulating the Macrophage Response to Gram Positive Bacteria. Genetics 2016;204(1):327-336. RD834515 (Final)
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  • Journal Article Breton CV, Marsit CJ, Faustman E, Nadeau K, Goodrich JM, Dolinoy DC, Herbstman J, Holland N, LaSalle JM, Schmidt R, Yousefi P, Perera F, Joubert BR, Wiemels J, Taylor M, Yang IV, Chen R, Hew KM, Freeland DM, Miller R, Murphy SK. Small-magnitude effect sizes in epigenetic end points are important in children's environmental health studies:the Children's Environmental Health and Disease Prevention Research Center's Epigenetics Working Group. Environmental Health Perspectives 2017;125(4):511-526. RD834515 (Final)
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  • 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 Szefler SJ, Dakhama A. New insights into asthma pathogenesis and treatment. Current Opinion in Immunology 2011;23(6):801-807. RD834515 (2011)
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  • Journal Article Szefler SJ. Advancing asthma care: the glass is only half full! Journal of Allergy and Clinical Immunology 2011;128(3):485-494. RD834515 (2011)
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  • Journal Article Szefler SJ. Advances in pediatric asthma in 2011: moving forward. Journal of Allergy and Clinical Immunology 2012;129(1):60-68. RD834515 (2011)
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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 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 (Final)
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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)
    RD834515 (2014)
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    RD834515C001 (2014)
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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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  • Journal Article Yang IV, Tomfohr J, Singh J, Foss CM, Marshall HE, Que LG, McElvania-Tekippe E, Florence S, Sundy JS, Schwartz DA. The clinical and environmental determinants of airway transcriptional profiles in allergic asthma. American Journal of Respiratory and Critical Care Medicine 2012;185(6):620-627. RD834515 (Final)
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  • Journal Article Julian CG, Yang IV, Browne VA, Vargas E, Rodriguez C, Pedersen BS, Moore LG, Schwartz DA. Inhibition of peroxisome proliferator-activated receptor gamma: a potential link between chronic maternal hypoxia and impaired fetal growth. FASEB Journal 2014;28(3):1268-1279. RD834515 (Final)
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  • Journal Article Kelada SN, Carpenter DE, Aylor DL, Chines P, Rutledge H, Chesler EJ, Churchill GA, Pardo-Manuel de Villena F, Schwartz DA, Collins FS. Integrative genetic analysis of allergic inflammation in the murine lung. American Journal of Respiratory Cell and Molecular Biology 2014;51(3):436-445. RD834515 (Final)
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  • Journal Article Liang L, Willis-Owen SAG, Laprise C, Wong KCC, Davies GA, Hudson TJ, Binia A, Hopkin JM, Yang IV, Grundberg E, Busche S, Hudson M, Ronnblom L, Pastinen TM, Schwartz DA, Lathrop GM, Moffatt MF, Cookson W. An epigenome-wide association study of total serum immunoglobulin E concentration. Nature 2015;520(7549):670-674. RD834515 (Final)
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  • Journal Article Eyring KR, Pedersen BS, Yang IV, Schwartz DA. In Utero Cigarette Smoke Affects Allergic Airway Disease But Does Not Alter the Lung Methylome. PloS one 2015;10(12):e0144087 (10 pp.). RD834515 (Final)
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  • Journal Article Julian CG, Pedersen BS, Salmon CS, Yang IV, Gonzales M, Vargas E, Moore LG, Schwartz DA. Unique DNA Methylation Patterns in Offspring of Hypertensive Pregnancy. Clinical and Translational Science 2015;8(6):740-745. RD834515 (Final)
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  • Journal Article Yang IV, Pedersen BS, Liu A, O’Connor GT, Teach SJ, Kattan M, Misiak RT, Gruchalla R, Steinbach SF, Szefler SJ, Gill MA, Calatroni A, David G, Hennessy CE, Davidson EJ, Zhang W, Gergen P, Togias A, Busse WW, Schwartz DA. DNA methylation and childhood asthma in the inner city. Journal of Allergy and Clinical Immunology 2015;136(1):69-80. RD834515 (Final)
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  • Journal Article Lai PS, Liang L, Cibas ES, Liu AH, Gold DR, Baccarelli A, Phipatanakul W. Alternate methods of nasal epithelial cell sampling for airway genomic studies. Journal of Allergy and Clinical Immunology 2015;136(4):1120-1123.e4. RD834515 (Final)
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  • Journal Article Yang IV, Richards A, Davidson EJ, Stevens AD, Kolakowski CA, Martin RJ, Schwartz DA. The nasal methylome: a key to understanding allergic asthma. American Journal of Respiratory and Critical Care Medicine 2017;195(6):829-831. RD834515 (Final)
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  • Journal Article Yang IV, Pedersen BS, Liu AH, O'Connor GT, Pillai D, Kattan M, Misiak RT, Gruchalla R, Szefler SJ, Khurana Hershey GK, Kercsmar C, Richards A, Stevens AD, Kolakowski CA, Makhija M, Sorkness CA, Krouse RZ, Visness C, Davidson EJ, Hennessy CE, Martin RJ, Togias A, Busse WW, Schwartz DA. The nasal methylome and childhood atopic asthma. Journal of Allergy and Clinical Immunology 2017;139(5):1478-1488. RD834515 (Final)
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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, human health, scientific discipline, health, RFA, biology, health risk assessment, children's health, allergens/asthma, asthma indices, intervention;, RFA, Health, Scientific Discipline, HUMAN HEALTH, Health Risk Assessment, Allergens/Asthma, Health Effects, Children's Health, Biology, asthma, sensitive populations, asthma triggers, endotoxin, asthma indices, children, airway inflammation, allergic response

    Relevant Websites:

    National Jewish Health: Children's Environmental Health Center Exit

    Progress and Final Reports:

    Original Abstract
  • 2010 Progress Report
  • 2012 Progress Report
  • 2013 Progress Report
  • 2014 Progress Report
  • 2015 Progress Report
  • Final Report
  • 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