2010 Progress Report: Environmental Determinants of Early Host Response to RSV

EPA Grant Number: RD834515C002
Subproject: this is subproject number 002 , established and managed by the Center Director under grant RD834515
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: Denver Children’s Environmental Health Center - Environmental Determinants of Airway Disease in Children
Center Director: Schwartz, David A.
Title: Environmental Determinants of Early Host Response to RSV
Investigators: Schwartz, David A.
Current Investigators: Schwartz, David A. , White, Carl W. , Dakhama, Azzeddine , Yang, Jing , Loader, Joan , Correll, Kelly , Gabehart, Kelsa
Institution: National Jewish Health
Current Institution: National Jewish Health , National Jewish Medical and Research Center , University of Colorado at Denver , University of North Carolina at Charlotte
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, 2010 through June 21,2011
RFA: Children's Environmental Health and Disease Prevention Research Centers (with NIEHS) (2009) RFA Text |  Recipients Lists
Research Category: Children's Health , Health


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.

Progress Summary:

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. Our initial studies, using pathway focused qPCR arrays, have shown significant changes in TLR expression in the airways of newborn mice at 24 h after postnatal ozone exposure. Analyses of lung tissues collected from these mice showed a significant thickening of the alveolar septae. This thickening was associated with peripheral (parenchymal) airway tissue infiltration with neutrophils, and was not due to cell proliferation or accumulation of myofibroblasts within the alveolar wall tissue. However, unlike ozone-exposed dam (mothers) where large numbers of neutrophils were recovered in the bronchoalveolar lavage (BAL) fluids, newborn mice showed only few neutrophils in their BAL. Comparison of the results of ozone exposure between different age groups of mice (i.e., 1, 2, 3, and 6 weeks) further established an age-dependent increase in airway responses to ozone. Thus, as the lung developed, the neutrophilic response increased and was associated with greater lung permeability and anti-oxidant response.

Depletion of neutrophils in the 3 or 6 weeks old mice did not alter ozone-induced lung permeability, suggesting that this alteration develops independent of neutrophil recruitment/accumulation in the airways of these mice. Studies of airway function are currently ongoing, as planned, to define the nature and extent of ozone-induced airways dysfunction that may associate with neutrophil accumulation in peripheral airways or lung permeability and tissue damage in central/proximal airways, following ozone exposure. To further define the effects of postnatal ozone exposure on the developing newborn mouse lung, we used a global approach of gene  expression analysis to identify the genes and pathways that are perturbed by ozone. A large number of genes were found to be downregulated (n=115) while others were upregulated (n=63) at the mRNA level, following ozone exposure. In addition to their functional role, some of these genes may also serve as reliable markers of biological response to ozone exposure. Gene expression pathway analyses revealed that ozone exposure inhibited a large number of genes (at least 25) involved in cell cycle, repair, cellular movement, cellular assembly and reorganization. Other pathways including cellular development, inflammatory response, cell-to-cell signaling and interaction also were significantly modified after ozone exposure.

Future Activities:

Complete Aim 1 by summer 2011 and publish results by the end of 2011. Initiate Aim 2 studies in June and pursue the sub-aims as planned in the original application.

Journal Articles:

No journal articles submitted with this report: View all 23 publications for this subproject

Supplemental Keywords:

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

Relevant Websites:

Children's Environmental Health Center (CEHC) - National Jewish HealthExit EPA Disclaimer

Progress and Final Reports:

Original Abstract
  • 2011
  • 2012
  • 2013
  • 2014 Progress Report
  • 2015 Progress Report
  • Final

  • Main Center Abstract and Reports:

    RD834515    Denver Children’s Environmental Health Center - Environmental Determinants of Airway Disease in Children

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    RD834515C001 Endotoxin Exposure and Asthma in Children
    RD834515C002 Environmental Determinants of Early Host Response to RSV
    RD834515C003 Environmental Determinants of Host Defense