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Final Report: The Etiology and Pathogenesis of Airway Disease in Children from Rural Communities
EPA Grant Number: R826711Center: University of Iowa Children's Environmental Airway Disease Center
Center Director: Hunninghake, Gary W.
Title: The Etiology and Pathogenesis of Airway Disease in Children from Rural Communities
Investigators: Hunninghake, Gary W. , Chrischilles, Elizabeth , Denning, Gerene , Merchant, James A. , Nauseef, William , Schwartz, David
Institution: University of Iowa
EPA Project Officer: Fields, Nigel
Project Period: August 1, 1998 through July 31, 2003
Project Amount: $2,660,847
RFA: Centers for Children's Environmental Health and Disease Prevention Research (1998)
Research Category: Children's Health , Health Effects
Description:
Objective:The objective of this research project was to investigate the etiology and pathogenesis in children from rural communities. During Year 5 of the Children’s Environmental Airway Disease Center at the University of Iowa, substantial progress has taken place. The four funded projects in the Center have made excellent progress and have met all of their goals for Year 4. In this regard, a number of publications either have been submitted, accepted, or published. The investigators also have received a substantial number of invitations to present their results at national and international meetings. Finally, the overall structure and necessary interactions within the Center ensured the continued success of the program. Another important evidence of the health of the program is that the Center has provided some financial support for exciting new programs that were not described in the original application but which will interface closely with existing projects and provide new directions for research. In Year 1, we were able to provide support for a Dr. Moreland, a promising Assistant Professor in Pediatrics, to pursue studies on the role of adhesion molecules in airway inflammation. She has found that ICAM-1 and the B integrins are essential to neutrophil recruitment. In Years 2 and 3, we provided support for Dr. Carter, who is a promising new investigator in the Department of Medicine. He has found that endotoxin increases the replication of viruses in airway epithelia. Drs. Hunninghake, Nauseef, and Schwartz all are evaluating the role of toll-4 in LPS signaling. The trainee who is currently being supported, Kevin M. Kelly, is being considered for an appointment in the College of Public Health. He is working with Dr. Chrischilles on Project 1. Each of these individuals continues research related to their training and this Center.
Summary/Accomplishments (Outputs/Outcomes):The Children’s Environmental Airway Disease Center at Iowa strengthens our research efforts related to environmental airway disease. The program is energetic, imaginative, cohesive, and productive. In the following paragraphs, the highlights of the accomplishments of various components of the program will be described. More detailed progress reports can be found in the individual Final Reports for R826711C001 through R826711C004 .
Project 1: Mechanisms That Initiate, Promote, and Resolve Grain Dust Induced Inflammation
The major strength of these studies is that they are modeled on the physiologically relevant concept that understanding grain dust-induced asthma will require understanding the effects of intact dust on the human airway. They also represent collaborative endeavors between the laboratories of Drs. Nauseef, Denning, Moreland, Weiss, and Schwartz. Finally, they include parallel studies with mouse and human model systems.
Project 2: Multicomponent Intervention Study of Asthma in Children From Rural Communities: The Rural Health Study
There are conflicting findings about the prevalence of asthma among farm and nonfarm children.
Objectives. We sought to estimate asthma prevalence and morbidity and determine differences between farm and nonfarm children.
Methods. The study population consisted of all children aged 6 to 14 years enrolled in 10 school districts in 2 noncontiguous rural Iowa counties from 2000 through 2002. The mailed parental screening questionnaire included the International Study of Asthma and Allergies in Childhood core questionnaire, items from the Functional Severity Index, and items on physician diagnosis and medication and urgent care use.
Results. The response rate was 86.6 percent. The 12-month prevalence of wheeze was 19.1 percent. Self-reported physician diagnosis of asthma was reported by 13.4 percent. On multivariable analysis controlling for age, sex, and county, children who lived on farms were less likely than those who lived in town to have ever wheezed (odds ratio, 0.71; 95% CI, 0.58-0.87) or to have wheezed during the past year (odds ratio, 0.77; 95% CI, 0.60-0.98). This protective association with farming, however, was observed only in one of the study counties. Among those who wheezed, farm and nonfarm children were equally likely to have been given a diagnosis of asthma and had comparable morbidity.
Conclusion. By using a standardized questionnaire with a high response rate in this large, rural, population-based study, asthma prevalence rivaled that in large Midwestern cities. Unmeasured risk factors might account for the apparent protective effect in Keokuk County. These findings cast doubt on a protective effect of rural life for the development of childhood asthma.
Project 3: Role of Respiratory Syncytical Virus (RSV) Infection and Endotoxin in Airway Inflammation
Previously, we have shown in a model of hypersensitivity pneumonitis that Th1-biased C57BL/6 mice are susceptible and Th2-biased DBA/2 mice are resistant to disease. We also showed that this was explained in part by differential regulation of IL-12 by IL-4. For these reasons, we postulated that C57BL/6 and DBA/2 mice differentially express IL-4. In this study, we show that C57BL/6 immune cells express Th2 but not Th1 cytokines at lower levels than DBA/2 cells. We also found that C57BL/6 splenocytes exhibit decreased mRNA stability of Th2 cytokines, relative to DBA/2 splenocytes. Stability of IL-2 and IFN-gamma were similar in the two strains of mice. Differences in Th2 cytokine mRNA stability between C57BL/6 and DBA/2 cells were not a result of sequence polymorphism at specific regions of the IL-4/IL-13 locus. Furthermore, expression of Th1- and Th2-specific transcription factors T-bet and GATA-3, as well as the nuclear factor of activated T cells transcription factor, NFATc, was not significantly different between the two mice. Our data suggest that decreased mRNA stability of Th2 cytokines in C57BL/6 splenocytes may underlie the differential susceptibility to hypersensitivity pneumonitis between C57BL/6 and DBA/2 mice. Moreover, our results indicate that regulation of mRNA stability may serve as an important mechanism underlying Th1/Th2 immune polarization.
Project 4: A Model to Study the Development of Persistent Environmental Airway Disease
We investigated the development of airway hyperreactivity (AHR) and inflammation in the lungs of nine genetically diverse inbred strains of mice [129/SvIm, A/J, BALB/cJ, BTBR+(T)/tf/tf, CAST/Ei, C3H/HeJ, C57BL/6J, DBA/2J, and FVB/NJ] after sensitization and challenge with ovalbumin (OVA). At 24, 48, and 72 hours post-OVA exposure, the severity of AHR and eosinophilic inflammation of the mouse strains ranged from relatively unresponsive to responsive. The severity of the airway eosinophilia of some strains did not correlate clearly with the development of AHR. The temporal presence of T helper type 2 cytokines in lung lavage fluid also varied markedly among the strains. The levels of IL-4 and IL-13 generally were increased in the strains with the highest airway eosinophilia at 24 and 72 hours postexposure, respectively; the levels of IL-5 were increased significantly in most of the strains with airway inflammation over the 72-hour time period. The differences of physiological and biological responses among the inbred mouse strains after OVA sensitization and challenge support the hypothesis that genetic factors contribute, in part, to the development of allergen-induced airway disease.
Administrative Core
The administrative core has functioned at a high level during the past year. The core has provided all of the necessary specimens to the projects. The administrative core has assisted all of the projects, arranged monthly scientific meetings of the investigators, and distributed funds to the projects.
Collaboration Within the Children’s Environmental Airway Disease Center. We are very pleased with the collaborations that we have. The principal investigators (PIs) and their laboratories meet on a monthly basis to share ideas and to obtain feedback on their projects. Two of the reasons for this level of interaction is the scientific focus of the program, and the resources and environment that the SCOR has provided for the participating investigators.
Collaboration With Other Children’s Environmental Health Programs. The Children’s Environmental Health Program Center at Iowa has established a listserv to enhance communication between centers and is looking forward to interacting with the other centers. We have established collaborations with investigators at the University of Southern California and Johns Hopkins University, both focused on the role of endotoxin in environmental airway disease. It is anticipated that these collaborations will provide a mechanism for other Center investigators to interact scientifically. All of the PIs in the Iowa Center will participate in the inter-Center meeting this year. The investigators at Iowa already have met to discuss areas for possible collaborations.
Journal Articles: 32 Displayed | Download in RIS Format
| Other center views: | All 33 publications | 32 publications in selected types | All 32 journal articles |
| Type | Citation | ||
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Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, Jones M, Frees K, Watt JL, Schwartz DA. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nature Genetics 2000;25(2):187-191. |
R826711 (Final) R826711C001 (2000) R826711C002 (2000) R826711C004 (Final) |
not available |
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Brass DM, Savov JD, Gavett SH, Haykal-Coates N, Schwartz DA. Subchronic endotoxin inhalation causes chronic airway disease. American Journal of Physiology-Lung Cellular and Molecular Physiology 2003;285(6):L755-L761. |
R826711 (Final) R826711C004 (Final) |
not available |
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Butler NS, Monick MM, Yarovinsky TO, Powers LS, Hunninghake GW. Altered IL-4 mRNA stability correlates with Th1 and Th2 bias and susceptibility to hypersensitivity pneumonitis in two inbred strains of mice. Journal of Immunology 2002;169(7):3700-3709. |
R826711 (Final) R826711C003 (Final) |
not available |
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Carter AB, Donohue MR, Knudtson KL, Gudmundsson G, Monick MM, Hunninghake GW. Endotoxin augments viral replication and the inflammatory response in respiratory syncytial virus-infected epithelium. Journal of Immunology. |
R826711C001 (2000) |
not available |
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Chrischilles E, Ahrens R, Kuehl A, Kelly K, Thorne P, Burmeister L, Merchant J. Asthma prevalence and morbidity among rural Iowa schoolchildren. Journal of Allergy and Clinical Immunology 2004;113(1):66-71 and erratum in Journal of Allergy and Clinical Immunology 113(3):391. |
R826711 (Final) R826711C002 (Final) |
not available |
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George CL, Jin H, Wohlford-Lenane CL, O’Neill ME, Phipps JC, O’Shaughnessy P, Kline JN, Thorne PS, Schwartz DA. Endotoxin responsiveness and subchronic grain dust-induced airway disease. American Journal of Physiology-Lung Cellular and Molecular Biology 2001;280(2):L203-L213. |
R826711 (Final) R826711C001 (2000) R826711C002 (2000) R826711C004 (Final) |
not available |
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George CL, White M, O’Neill ME, Thorne PS, Schwartz DA, Snyder JM. Altered surfactant protein A gene expression and protein metabolism associated with repeat exposure to inhaled endotoxin. American Journal of Physiology-Lung Cellular and Molecular Physiology 2003;285(6):L1337-L1344. |
R826711 (Final) R826711C004 (Final) |
not available |
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Hollingsworth JW, Cook DN, Brass DM, Walker JK, Morgan DL, Foster WM, Schwartz DA. The role of toll-like receptor 4 in environmental airway injury in mice. American Journal of Respiratory and Critical Care Medicine 2004;170(2):106-107. |
R826711 (Final) R826711C004 (Final) |
not available |
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Kline JN, Jagielo PJ, Watt JL, Schwartz DA. Bronchial hyperreactivity is associated with enhanced grain dust-induced airflow obstruction. Journal of Applied Physiology 2000;89(3):1172-1178. |
R826711 (Final) R826711C001 (2000) R826711C002 (2000) R826711C004 (Final) |
not available |
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Kline JN, Cowden JD, Hunninghake GW, Watt JL, Wohlford-Lenane CL, Powers LS, Jones MP, Schwartz DA. Variable airway responsiveness to inhaled lipopolysaccharide. American Journal of Respiratory and Critical Care Medicine 1999;160(1):297-303, 1999. |
R826711C001 (2000) R826711C002 (2000) |
not available |
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Lorenz E, Jones M, Wohlford-Lenane C, Meyer N, Frees KL, Arbour NC, Schwartz DA. Genes other than TLR4 are involved in the response to inhaled LPS. American Journal of Physiology-Lung Cellular and Molecular Physiology 2001;281(5):L1106-L1114. |
R826711 (Final) R826711C004 (Final) |
not available |
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Monick MM, Staber JM, Thomas KW, Hunninghake GW. Respiratory syncytial virus infection results in activation of multiple protein kinase C isoforms leading to activation of mitogen-activated protein kinase. Journal of Immunology 2001;166(4):2681-2687. |
R826711 (Final) R826711C001 (2000) R826711C003 (Final) |
not available |
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Monick MM, Yarovinsky TO, Powers LS, Butler NS, Carter AB, Gudmundsson G, Hunninghake GW. Respiratory syncytial virus up-regulates TLR4 and sensitizes airway epithelial cells to endotoxin. Journal of Biological Chemistry 2003;278(52):53035-53044. |
R826711 (Final) R826711C003 (Final) |
not available |
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Moreland JG, Fuhrman RM, Wohlford-Lenane CL, Quinn TJ, Benda E, Pruessner JA, Schwartz DA. TNF-α and IL-1β are not essential to the inflammatory response in LPS -induced airway disease. American Journal of Physiology-Lung Cellular and Molecular Biology 2001;280(1):L173-L180. |
R826711 (Final) R826711C001 (2000) R826711C002 (2000) R826711C004 (Final) |
not available |
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Moreland JG, Fuhrman RM, Pruessner JA, Schwartz DA. CD11b and intercellular adhesion molecule-1 are involved in pulmonary neutrophil recruitment in lipopolysaccharide-induced airway disease. American Journal of Respiratory Cell and Molecular Biology 2002;27(4):474-480. |
R826711 (Final) R826711C004 (Final) |
not available |
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Moreland JG, Bailey G, Nauseef WM, Weiss JP. Organism-specific neutrophil-endothelial cell interactions in response to Escherichia coli, Streptococcus pneumoniae, and Staphylococcus aureus. Journal of Immunology 2004;172(1):426-432. |
R826711 (Final) R826711C001 (Final) |
not available |
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Quinn TJ, Taylor S, Wohlford-Lenane CL, Schwartz DA. IL-10 reduces grain dust-induced airway inflammation and airway hyperreactivity. Journal of Applied Physiology 2000;88(1):173-179. |
R826711 (Final) R826711C001 (2000) R826711C002 (2000) R826711C004 (Final) |
not available |
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Savov JD, Gavett SH, Brass DM, Costa DL, Schwartz DA. Neutrophils play a critical role in the development of LPS-induced airway disease. American Journal of Physiology-Lung Cellular and Molecular Physiology 2002;283(5):L952-L962. |
R826711 (Final) R826711C004 (Final) |
not available |
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Savov JD, Brass DM, Berman KG, McElvania E, Schwartz DA. Fibrinolysis in LPS -induced chronic airway disease. American Journal of Physiology-Lung Cellular and Molecular Physiology 2003;285(4):L940-L948. |
R826711 (Final) R826711C004 (Final) |
not available |
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Savov JD, Whitehead GS, Wang J, Liao G, Usuka J, Peltz G, Foster WM, Schwartz DA. Ozone-induced acute pulmonary injury in inbred mouse strains. American Journal of Respiratory Cell and Molecular Biology 2004;31(1):69-77. |
R826711 (Final) R826711C004 (Final) |
not available |
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Schwartz DA, Wohlford-Lenane CL, Quinn TJ, Krieg AM. Bacterial DNA or oligonucleotides containing unmethylated CpG motifs can minimize LPS-induced inflammation in the lower respiratory tract through an IL-12 dependent pathway. Journal of Immunology 1999;163:224-231. |
R826711C001 (2000) R826711C002 (2000) |
not available |
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Schwartz DA. Etiology and pathogenesis of airway disease in children and adults from rural communities. Environmental Health Perspectives, 1999; 107 (Suppl 3):393-401. |
R826711C001 (2000) R826711C002 (2000) |
not available |
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Schwartz DA. Does inhalation of endotoxin cause asthma? American Journal of Respiratory and Critical Care Medicine 2001;163(2):305-306. |
R826711 (Final) R826711C004 (Final) |
not available |
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Schwartz DA, Christ WJ, Kleeberger SR, Wohlford-Lenane CL. Inhibition of LPS -induced airway hyperresponsiveness and airway inflammation by LPS antagonists. American Journal of Physiology-Lung Cellular and Molecular Physiology 2001;280(4):L771-L778. |
R826711 (Final) R826711C004 (Final) |
not available |
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Thomas KW, Monick MM, Staber JM, Yarovinsky TO, Carter AB, Hunninghake GW. RSV inhibits apoptosis and induces NF-κB activity through a PI-3K dependent pathway. Journal of Biological Chemistry 2002;277(1):492-501. |
R826711 (Final) R826711C003 (Final) |
not available |
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Walker JK , Fong AM, Lawson BL, Savov JD, Patel DD, Schwartz DA, Lefkowitz RJ. Beta-arrestin-2 regulates the development of allergic asthma. The Journal of Clinical Investigation 2003;112(4):566-574. |
R826711 (Final) R826711C004 (Final) |
not available |
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Warshamana GS, Pociask DA, Sime P, Schwartz DA, Brody AR. Susceptibility to asbestos-induced and transforming growth factor-beta 1-induced fibroproliferative lung disease in two strains of mice. American Journal of Respiratory Cell and Molecular Biology 2002;27(6):705-713. |
R826711 (Final) R826711C004 (Final) |
not available |
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Whitehead GS, Walker JK , Berman KG, Foster WM, Schwartz DA. Allergen -induced airway disease is mouse strain dependent. American Journal of Physiology-Lung Cellular and Molecular Physiology 2003;285(1):L32-L42. |
R826711 (Final) R826711C004 (Final) |
not available |
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Wohlford-Lenane CL, Deetz DC, Schwartz DA. Cytokine gene expression following inhalation of corn dust. American Journal of Physiology: Lung Cell Molecular Biology 1999;276:L736-L743. |
R826711C001 (2000) R826711C002 (2000) |
not available |
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Zeldin DC, Wohlford-Lenane C, Chulada P, Bradbury JA, Scarborough PE, Roggli V, Langenbach R, Schwartz DA. Airway inflammation and responsiveness in prostaglandin H synthase-deficient mice exposed to bacterial lipopolysaccharide. American Journal of Respiratory Cell and Molecular Biology 2001;25(4):457-465. |
R826711 (Final) R826711C004 (Final) |
not available |
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Chen W, Monica MM, Carter AB, Hunninghake GW. Activation of ERK2 by respiratory syncytial virus in A549 cells is linked to the production of interleukin 8. Experimental Lung Research 2000;6(1):13-26. |
R826711 (Final) R826711C001 (2000) R826711C003 (Final) |
not available |
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Chen W, Hunninghake GW. Effects of ragweed and Th-2 cytokines on the secretion of IL-8 in human airway epithelial cells. Experimental Lung Research 2000;26(4):229-239. |
R826711 (Final) R826711C001 (2000) R826711C003 (Final) |
not available |
children’s health, human health risk assessment, air pollution, airway disease, airway inflammation, allergen, allergic response, assessment of exposure, asthma, asthma indices, asthma triggers, asthmatic children, childhood respiratory disease, children’s environmental health, environmental health, environmental health hazard, environmental risks, exposure, exposure assessment, grain dust, harmful environmental agents, health effects, human exposure, human health risk, persistent environmental airway disease, respiratory problems,
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Geographic Area, Scientific Discipline, Health, RFA, Biology, Risk Assessments, Health Risk Assessment, Epidemiology, Children's Health, Environmental Chemistry, Allergens/Asthma, State, exposure assessment, asthma indices, allergen, health effects, respiratory problems, children's environmental health, asthmatic children, assessment of exposure, childhood respiratory disease, farmworkers, harmful environmental agents, human health risk, genetic susceptibility, epidemeology, agricultural community, sensitive populations, grain dust, environmental health, air pollution, airway disease, children, environmental risks, IOWA (IA), exposure, children's vulnerablity, environmental health hazard, asthma triggers, allergic response, persistent environmental airway disease, asthma, human exposure, Human Health Risk Assessment
Progress and Final Reports:
2000 Progress Report
2001 Progress Report
Original Abstract
Subprojects under this Center:
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R826711C001 Mechanisms that Initiate, Promote, and Resolve Grain Dust/LPS Induced Inflammation
R826711C002 Multi-component Intervention Study of Asthma in Children from Rural Communities
R826711C003 Role of RSV Infection and Endotoxin in Airway Inflammation
R826711C004 A Model to Study the Development of Persistent Environmental Airway Disease