Final Report: Mechanisms of Particulate-Induced Allergic Asthma

EPA Grant Number: R832139C003
Subproject: this is subproject number 003 , established and managed by the Center Director under grant R832139
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: Johns Hopkins Center for Childhood Asthma in the Urban Environment
Center Director: Breysse, Patrick N.
Title: Mechanisms of Particulate-Induced Allergic Asthma
Investigators: Wills-Karp, Marsha
Institution: The Johns Hopkins University
EPA Project Officer: Callan, Richard
Project Period: November 1, 2003 through October 31, 2008 (Extended to October 31, 2010)
RFA: Centers for Children's Environmental Health and Disease Prevention Research (2003) RFA Text |  Recipients Lists
Research Category: Children's Health , Health Effects , Health


[From Main Project # R832139-Final Report]: The long term goal of the Center for Childhood Asthma in the Urban Environment was to examine how exposures to environmental pollutants and allergens may relate to airway inflammation and respiratory morbidity in children with asthma living in the inner city of Baltimore, and to search for new ways to reduce asthma morbidity by reducing exposure to these agents.
The third project examines the mechanisms by which particulate matter may exacerbate an allergen-driven response in the airways. The fourth project will examine the effects of environmental particulates on the in vitro maturation of peripheral blood monocytes to dendritic cells.

Summary/Accomplishments (Outputs/Outcomes):

Project 3 has examined the mechanisms by which urban airborne particulate matter may exacerbate an allergen-driven inflammatory response in the airways: To determine the relationship between exposure to airborne indoor PM and asthma morbidity, a comparison was made of the biological effects of PM collected in homes of children with mild and severe asthma, stratified for the presence of smokers in the home, using the development of asthma symptoms in mice as a readout system. To determine the interaction with genetic factors, environmental exposure to allergens, and environmental PM exposures which contribute to asthma morbidity, we examined the biological effects of exposure to indoor urban Baltimore PM in non-allergic strains of mice. To determine the role of complement factor 3 in mediating urban indoor PM-induced inflammation and/or exacerbations of allergic asthmatic symptoms, we compared the biological effects of PM exposure in C3 deficient and wildtype mice.
We found that PM induces significant elevations in the numbers of lung derived myeloid DC as compared to the plasmacytoid subset. We found that plasmactyoid DCs confer tolerance to the development of allergic responses suggesting that PM exposure may enhance allergic responses by altering the balance of immunogenic to tolerogenic DCs present in the lung. We cultured mDCs isolated from the bone marrow (BMDDC) of A/J mice and measured the production of the Th1directing cytokine, IL-12 and the Th2-directing cytokines, IL-6. Interestingly, we find that AUB-conditioned epithelial supernatants preferentially induce the production of the Th2 directing cytokine, IL-6.
These results suggest that AUB may induce the production of factors by the airway epithelium that activate DCs to provide Th2 promoting signals to T cells. Our studies suggest that AUB induces changes in the airway epithelial that skew the immune response towards a Th2 response. Studies are currently underway to determine whether differences in complement family genes, oxidative stress genes or prostaglandin genes play a role in the differential susceptibility of the two murine strains to AUB-induced dendritic cell activation and AHR. In addition, we have found that the development of AHR, is dependent activation of adaptive immune responses as Rag1-/- mice, which are devoid of lymphocytes, do not develop AHR in response to AUB exposure. Surprisingly airway inflammation is only partially dependent upon lymphocytes, suggesting that innate immune pathways are also activated in the airways in response to AUB.


To our knowledge these are the first studies to demonstrate that ambient particulates can directly induce the symptoms of asthma. Secondly, our finding that PM skews epithelial-dendritic cell interactions such that DC preferentially produce Th2/Th17-directing cytokines through oxidative signaling pathways provides a potential mechanism by which particulates induce AHR and inflammation as well as provide a potential therapeutic target.

Journal Articles on this Report : 1 Displayed | Download in RIS Format

Other subproject views: All 18 publications 18 publications in selected types All 18 journal articles
Other center views: All 113 publications 113 publications in selected types All 110 journal articles
Type Citation Sub Project Document Sources
Journal Article Saunders V, Breysse P, Clark J, Sproles A, Davila M, Wills-Karp M. Particulate matter-induced airway hyperresponsiveness is lymphocyte dependent. Environmental Health Perspectives 2010;118(5):640-646. R832139 (Final)
R832139C003 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: ResearchGate - Abstract & Full Text PDF
  • Supplemental Keywords:

    RFA, Scientific Discipline, Health, Air, Geographic Area, HUMAN HEALTH, particulate matter, Health Risk Assessment, State, Health Effects, Allergens/Asthma, asthma, children's health, asthma triggers, air toxics, exposure, air pollution, children, air pollutant, human exposure, airborne pollutants, Maryland (MD), PM, allergens

    Progress and Final Reports:

    Original Abstract
  • 2004 Progress Report
  • 2005 Progress Report
  • 2006 Progress Report
  • 2007 Progress Report
  • 2008
  • 2009

  • Main Center Abstract and Reports:

    R832139    Johns Hopkins Center for Childhood Asthma in the Urban Environment

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R832139C001 The Epidemiology of Susceptibility to Airborne Particulates and Allergens to Asthma in African Americans
    R832139C002 A Randomized Controlled Trial of Behavior Changes in Home Exposure Control
    R832139C003 Mechanisms of Particulate-Induced Allergic Asthma
    R832139C004 Dendritic Cell Activation by Particulate Matter and Allergen