Grantee Research Project Results
2012 Progress Report: Endotoxin Exposure and Asthma in Children
EPA Grant Number: R834515Center: Denver Childrens Environmental Health Center - Environmental Determinants of Airway Disease in Children
Center Director: Guo, Yanbing
Title: Endotoxin Exposure and Asthma in Children
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, 2012 through June 21,2013
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 , Human Health
Objective:
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 an NIH-sponsored multi-center cohort of children with asthma (Childhood Asthma Management Program), which has tracked asthma severity for more than 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 is 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.
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, we developed and validated a Standard Operating Procedure to measure endotoxin using Recombinant Factor C, and established quality control parameters.
- Childhood Asthma Management Program (CAMP): Our CAMP investigation is the first study, to our knowledge, to clearly distinguish household endotoxin from mold exposure in children with asthma. By measuring endotoxin with the Recombinant Factor C (rFC) reagent specific for endotoxin (instead of the commonly used Limulus Amebocyte Lysate assay that detects both endotoxin and fungal glucans), and using separate mold exposure measures (i.e., mold plate counts), we determined the effects of household endotoxin and mold exposures on asthma severity. In fact, we found that higher endotoxin levels in baseline dust samples (n=962) were associated with less prednisone days (an indicator of severe asthma exacerbations), while high mold counts were associated with more prednisone days during the 4-year course of the study. Only weak correlations were found between log mold concentrations and endotoxin levels (unadjusted r=0.17; p=<0.0001). When the effects of endotoxin and mold exposures on prednisone days were assessed for each site (with both exposures in the model), endotoxin-associated reductions and mold-associated increases in prednisone days were found for five of the eight CAMP sites (Baltimore, Denver, San Diego, St. Louis, and Toronto), consistent with the overall model. We also have 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.
- Denver Panel Study (DPS): 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.
- Housing & Urban Development (HUD): 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 three levels: Education Only, Minor Remediation, and Moderate Remediation. 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. Endotoxin concentration was measured in 262 house dust samples collected from the general living area and participant’s bedroom. Seventy homes had all dust samples collected, meaning adequate dust samples for endotoxin measurement from both general living area and bedroom, before (Pre) and 6 months after (Post) remediation. Remediation did not significantly reduce house dust endotoxin levels measured 6 months later (Wilcoxon Rank Sums test).
Future Activities:
The coming year will be an active period of analyses and preparation of our findings for presentation and manuscript submissions. For the NIH funded CAMP study, the endotoxin exposure working group has completed its analyses, submitted this investigation for presentation at a premier meeting, and is in the final stages of manuscript preparation for submission. The CAMP TLR genetics working group is anticipating completion of their analyses and a manuscript submission of their findings. We have completed our collaborative investigation of endotoxin exposure and asthma outcomes in 150 inner city children in Baltimore (NIH funded MAACS Study: PI E. Matsui); a manuscript of our findings was submitted for publication. We also have completed collaborative investigation of endotoxin exposure and early childhood wheezing phenotypes in a Denver inner city pre-school cohort (NIH funded CAPS Study: PI M.D. Klinnert); we submitted this investigation for presentation at a premier meeting, and it is in the final stages of manuscript preparation for submission. What we have learned from our CAMP, MAACS, HUD and CAPS studies, and the other Projects and COTC in our CEHC, is informing and strengthening the development of our DPS longitudinal study planned for Years 4 – 5 of this grant.
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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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. |
R834515 (Final) |
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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. |
R834515 (Final) R835436 (2017) R836159 (2018) |
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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. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
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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. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
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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. |
R834515 (2011) R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C002 (2015) R834515C003 (2014) |
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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. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C002 (2015) R834515C003 (2014) |
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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. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
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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. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
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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. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
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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. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C003 (2014) R834515C003 (2016) |
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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. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
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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.). |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
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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. |
R834515 (2012) R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C001 (2015) R834515C002 (2014) R834515C003 (2014) R834510 (2014) |
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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. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
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Szefler SJ, Dakhama A. New insights into asthma pathogenesis and treatment. Current Opinion in Immunology 2011;23(6):801-807. |
R834515 (2011) R834515 (Final) |
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Szefler SJ. Advancing asthma care: the glass is only half full! Journal of Allergy and Clinical Immunology 2011;128(3):485-494. |
R834515 (2011) R834515 (Final) |
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Szefler SJ. Advances in pediatric asthma in 2011: moving forward. Journal of Allergy and Clinical Immunology 2012;129(1):60-68. |
R834515 (2011) R834515 (Final) |
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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. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
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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.. |
R834515 (Final) |
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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. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
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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. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
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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. |
R834515 (Final) |
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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. |
R834515 (Final) |
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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. |
R834515 (Final) |
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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. |
R834515 (Final) |
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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.). |
R834515 (Final) |
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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. |
R834515 (Final) |
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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. |
R834515 (Final) |
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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. |
R834515 (Final) |
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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. |
R834515 (Final) |
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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. |
R834515 (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, health, health effects, 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 responseRelevant Websites:
Denver Children's Environmental Health Center (CEHC) Exit
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).
R834515C001 Endotoxin Exposure and Asthma in Children
R834515C002 Environmental Determinants of Early Host Response to RSV
R834515C003 Environmental Determinants of Host Defense
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
- Final Report
- 2015 Progress Report
- 2014 Progress Report
- 2013 Progress Report
- 2011 Progress Report
- 2010 Progress Report
- Original Abstract
30 journal articles for this center