2004 Progress 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)
Project Period Covered by this Report: November 1, 2003 through October 31, 2004
RFA: Centers for Children's Environmental Health and Disease Prevention Research (2003) RFA Text |  Recipients Lists
Research Category: Children's Health , Health Effects , Health


The objectives of this research project are to: (1) establish a causal relationship between particulate matter (PM) exposure and asthma morbidity; and (2) determine the mechanisms by which PM elicits these effects.

Progress Summary:

To date, we have determined that a single (0.5 mg/mouse) intratracheal dose of PM collected in urban Baltimore induces significant increases in airway hyperresponsiveness (AHR), which is sustained over a 7-day period, returning to control levels at 14 days. The increase in AHR was preceded by dramatic increases in bronchoalveolar lavage granulocytes, particularly eosinophils. These physiological changes were associated with an early Th2 cytokine pattern (IL-5, IL-13, eotaxin), which shifted toward a Th1 pattern as AHR and granulocytes returned to normal levels. When the effects of ambient urban Baltimore (AUB) particulates were compared to two reference coal fly ash particulates, we found that AUB induced far more dramatic effects on AHR and airway inflammation than either of the reference particles. Finally, in a leaching experiment, we found that the active components of AUB are not water soluble, but remain particle-bound. We concluded from these studies that ambient PM can induce asthma-like parameters in naive mice, suggesting that PM exposure may contribute to increases in asthma prevalence.

As we recently have identified complement as a susceptibility gene for asthma in a murine model, we evaluated its role in PM-induced AHR. The responses to PM exposure were compared in complement factor 3 (C3)-deficient mice and their wild-type controls. Interestingly, C3-deficient mice did not develop AHR, whereas the wild-type mice developed significant AHR in response to particulate exposure. Immunostaining of lung sections with a fluorescent-labeled anti-C3 antibody revealed that C3 was deposited along the epithelial surface and in the smooth muscle layer. Thus, complement deposition may be a common mechanism by which airborne particles elicit allergic airway responses.

In another experiment, we compared the effects of PM collected in urban Baltimore with PM that was collected at the site of the World Trade Center (WTC) on September 11, 2001. Interestingly, although WTC PM elicited inflammation, it did not induce AHR as was observed with ambient Baltimore PM. Further characterization of the two sources of PM may reveal causative components of the Baltimore PM.

Because of these findings, we have proposed adding the following specific objectives:

  • Determine the relationship between exposure to airborne indoor PM and asthma morbidity by comparing the biological effects or 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.
  • Determine the interaction with genetic factors, environmental exposure to allergens, and environmental PM exposures that contribute to asthma morbidity by examining the biological effects of exposure to indoor urban Baltimore PM in nonallergic strains of mice.
  • Determine the role of C3 in mediating urban indoor PM-induced inflammation and/or exacerbations of allergic asthmatic symptoms by comparing the biological effects of PM exposure in C3-deficient and wild-type mice.

Findings, Relevance to Field

Our findings have several implications to the field of asthma. First, to our knowledge, they are the first studies to demonstrate that ambient particulates can directly induce the symptoms of asthma. Second, our finding that particulates induce C3 activation may provide a potential mechanism by which particulates induce AHR and inflammation as well as provide a potential therapeutic target.

Future Activities:

Our plans during the next 6 months include further study of the role of indoor particulates in PM-induced allergic airway responses. We plan to determine the source of C3 production as well as the potential mechanisms by which C3 may be cleaved.

In addition, we plan to collect PM by similar means as the AUB from indoor sources in inner-city homes and possibly from either a rural source or a source enriched for diesel particles such as the truck-only lane of the Baltimore Fort McHenry Tunnel. A comparison of different sources of the PM may provide further information regarding the biologically active components of the AUB.

Journal Articles on this Report : 3 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 Barnes KC, Caraballo L, Munoz M, Zambelli-Weiner A, Ehrlich E, Burki M, Jimenez S, Mathias RA, Stockton ML, Deindl P, Mendoza L, Hershey GK, Nickel R, Wills-Karp M. A novel promoter polymorphism in the gene encoding complement component 5 receptor 1 on chromosome 19q13.3 is not associated with asthma and atopy in three independent populations. Clinical and Experimental Allergy 2004;34(5):736-744. R832139 (2004)
R832139 (2005)
R832139 (2007)
R832139C003 (2004)
  • Abstract from PubMed
  • Journal Article Hawlisch H, Wills-Karp M, Karp CL, Kohl J. The anaphylatoxins bridge innate and adaptive immune responses in allergic asthma. Molecular Immunology 2004;41(2-3):123-131. R832139 (2004)
    R832139 (2005)
    R832139 (2007)
    R832139C003 (2004)
  • Abstract from PubMed
  • Journal Article Wills-Karp M, Ewart SL. Time to draw breath: asthma-susceptibility genes are identified. Nature Reviews Genetics 2004;5(5):376-387. R832139 (2004)
    R832139 (2005)
    R832139C003 (2004)
  • Abstract from PubMed
  • Supplemental Keywords:

    particulate matter, PM, airway hyperresponsiveness, AHR, asthma, complement factor 3, C3, children’s health, Baltimore,, 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
  • 2005 Progress Report
  • 2006 Progress Report
  • 2007 Progress Report
  • 2008
  • 2009
  • Final Report

  • 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