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. , Martyny, John W. , Murphy, Amy J , Rabinovitch, Nathan , Strand, Mathew J. , Van Dyke, Michael V.
Institution: National Jewish Health
EPA Project Officer: Louie, Nica
Project Period: June 22, 2010 through June 21, 2015 (Extended to June 21, 2017)
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:

Recently, a U.S.-wide survey linked household endotoxin exposure to asthma, making it a U.S. public health concern. However, it is not known whether ambient endotoxin exerts its pathogenic effects on asthma persistence, severity and/or causation. 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.

Approach:

We propose to study endotoxin-induced airway conditions in children through three complementary clinical investigations. First, we will capitalize 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 propose 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 will take 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.

Expected Results:

This combination of studies will 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 outcomes.


Journal Articles: 40 Displayed | Download in RIS Format

Other center views: All 59 publications 40 publications in selected types All 40 journal articles
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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. 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 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 Alper S, Warg LA, De Arras L, Flatley BR, Davidson EJ, Adams J, Smith K, Wohlford-Lenane CL, McCray PB, Jr., Pedersen BS, Schwartz DA, Yang IV. Novel Innate Immune Genes Regulating the Macrophage Response to Gram Positive Bacteria. Genetics. 2016;204(1):327-36. Epub 2016/07/01. doi:10.1534/genetics.115.185314. PubMed PMID:27356610; PMCID:PMC5012397. RD834515 (Final)
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    Journal Article Denver CEHC (RD83451501):Final Center Report Page 7 of 9. RD834515 (Final)
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    Journal Article Dutmer CM, Schiltz AM, Faino A, Rabinovitch N, Cho S-H, Chartier RT, Rodes CE, Thornburg JW, Liu AH. Accurate assessment of personal air pollutant exposures in inner-city asthmatic children. Journal of Allergy and Clinical Immunology 2015;35(2 Suppl):AB165. 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. J Allergy Clin Immunol. 2015;136(4):1120-3.e4. Epub 2015/06/04. doi:10.1016/j.jaci.2015.04.032. PubMed PMID:26037550; PMCID:PMC4600430. RD834515 (Final)
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    Journal Article Allergic Airway Disease In Mice. Am J Respir Crit Care Med 2012; 185:A4647. 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):670-4. Epub 2015/02/25. doi:10.1038/nature14125. PubMed PMID:25707804; PMCID:PMC4416961. RD834515 (Final)
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    Journal Article Reddy MB, Liu AH, Schiltz A, Forssen A, Klinnert MD. Cluster Analysis of an Inner-City Cohort of Infant Wheezers. J Allergy Clin Immunol 2014; 133(2):AB71. 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. The Journal of allergy and clinical immunology. 2015;136(1):69-80. doi:10.1016/j.jaci.2015.01.025. PubMed PMID:PMC4494877. RD834515 (Final)
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    Journal Article Covar RA, Forssen A, Szefler SJ, Schwartz DA, Liu AH. Divergent Effects of Endotoxin and Mold Exposure on Asthma Exacerbations In The Childhood Asthma Management Program (CAMP). J Allergy Clin Immunol 2014; 133:AB164. RD834515 (Final)
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    Journal Article Gabehart K, Correll KA, Yang J, Loader JE, White CW, Dakhama A. Effect Of Ozone Exposure On Established Denver CEHC (RD83451501):Final Center Report Page 7 of 9 Allergic Airway Disease In Mice. Am J Respir Crit Care Med 2012; 185:A4647. RD834515 (Final)
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    Journal Article Gabehart K, Correll KA, Yang J, Collins ML, Loader JE, White CW, Dakhama A. Effect of Postnatal Ozone Exposure on the Developing Lung. Am J Respir Crit Care Med 2011; 183:A3242. RD834515 (Final)
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    Journal Article Sordillo JE, Raby BA, Liu AH, Weiss ST, Gold DR, Litonjua AA. Genome wide, patway level gene by environment interactions in models of endotoxin exposure and asthma severity. Am J Resp Crit Care Med 189;2014:A3835. 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. Epub 2015/12/08. doi:10.1371/journal.pone.0144087. PubMed PMID:26642056; PMCID:PMC4671614. RD834515 (Final)
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    Journal Article Dutmer CM, Schiltz AM, Faino A, Cho SH, Chartier RT, Rodes CE, Szefler SJ, Schwartz DA, Thornburg JW, Liu AH. Increased asthma severity associated with personal air pollutant exposures in inner-city asthmatic children. American Journal of Respiratory and Critical Care Medicine 2015:191:A6268. 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:official publication of the Federation of American Societies for Experimental Biology. 2014;28(3):1268-79. Epub 2013/12/07. doi:10.1096/fj.13-239749. PubMed PMID:24307415; PMCID:PMC3929669. 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. Am J Respir Cell Mol Biol 2014; 51:436-45. [PMCID:PMC4189492]. RD834515 (Final)
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    Journal Article Gabehart K, Correll KA, Yang J, Loader JE, White CW, Dakhama A. Postnatal Ozone Exposure Enhances House Dust Mite Induced Airway Hyperresponsiveness Without Increasing Inflammation. J Allergy Clin Immunol 2012; 129(2) Suppl:A204. 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. Environ Health Perspect. 2017 Apr;125(4):511-526. doi:10.1289/EHP595. PMID:28362264 PMCID:PMC5382002 (https://www-ncbi-nlm-nih-gov.dartmouth.idm.oclc.org/pubmed/?term=PMC5382002). RD834515 (Final)
    R835442 (2017)
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    Journal Article Yang IV, Tomfohr J, Singh J, Foss CM, Marshall HE, Que, LG, Florence S, McElvania-Tekippe E, Sundy JS, Schwartz DA. The Clinical and Environmental Determinants of Airway Transcriptional Profiles in Allergic Asthma. Am J Respir Crit Care Med 2012; 185:620-627. [PMID:22246175]. 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. Am J Respir Crit Care Med. 2017;195(6):829-31. Epub 2017/03/16. doi:10.1164/rccm.201608-1558LE. PubMed PMID:28294656; PMCID:PMC5363969. RD834515 (Final)
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    Journal Article Warg LA, Oakes J, Burton R, Rutledge HR, Groshong S, Schwartz DA and Yang IV. The Role of the E2F1 Transcription Factor in the Innate Immune Response to Systemic LPS. Am J Physiol Lung Cell Mol Physiol 2012; 303:L391-400. [PMID:22707615]. 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. J Allergy Clin Immunol. 2016. Epub 2016/10/18. doi:10.1016/j.jaci.2016.07.036. PubMed PMID:27745942. 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):740-5. Epub 2015/11/08. doi:10.1111/cts.12346. PubMed PMID:26546417; PMCID:PMC4703563. 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;, RFA, Health, Scientific Discipline, HUMAN HEALTH, Health Risk Assessment, Allergens/Asthma, Health Effects, Children's Health, Biology, asthma, asthma triggers, sensitive populations, endotoxin, asthma indices, airway inflammation, children, allergic response

    Progress and Final Reports:

    2010 Progress Report
    2011 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