Grantee Research Project Results

2002 Progress Report: Mechanisms Of Particulate-Induced Allergic Asthma

EPA Grant Number: R826724C002
Subproject: this is subproject number 002 , established and managed by the Center Director under grant R826724
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: Center for the Study of Childhood Asthma in the Urban Environment
Center Director: Hansel, Nadia
Title: Mechanisms Of Particulate-Induced Allergic Asthma
Investigators: Wills-Karp, Marsha
Institution: The Johns Hopkins University
EPA Project Officer: Callan, Richard
Project Period: January 1, 1998 through January 1, 2002
Project Period Covered by this Report: January 1, 2001 through January 1, 2002
Project Amount: Refer to main center abstract for funding details.
RFA: Centers for Children's Environmental Health and Disease Prevention Research (1998) RFA Text |  Recipients Lists
Research Category: Children's Health , Human Health

Objective:

The objective of this project is to examine the mechanisms by which ambient particulate matter (PM) may exacerbate allergic airways disease, or play a role in the induction of an asthma-like phenotype in a murine model. The studies show that a single exposure to ambient PM (0.5mg, < 0. 8um diameter) collected in inner city Baltimore induces sustained airway hyperresponsiveness (AHR), and puhnonary inflammation (i.e. eosinophilia and neutrophilia) Conversely, these responses are not observed when animals are exposed to a reference source of fly ash. Interestingly, this phenotype is observed in all murine strains studied to date, although to varying degrees suggesting that genetic susceptibility to develop allergic airway responses is not required. Additionally, in an ongoing study, investigators results indicate that repeated exposure to low doses of PM (5 ug) may have a cumulative effect in the development of AHR accompanied by mild, but persistent eosinophilia. Studies are underway to investigate the role of different cell types such as eosinophils and macrophages in PM-induced airway responses. One of the most interesting findings is that PM-induced AHR appears to be dependent on the complement component (C3). Studies are underway to define the exact mechanisms by which complement activation mediates AHR.

The objectives have been expanded, due to investigators recent discovery of the importance of C5 in allergen-induced airway hyperresponsiveness. Investigators have added a specific aim to examine the role of complement components in airway hyperresponsiveness and airway inflammation induced by environmental particulates.

Progress Summary:

Progress has been made toward the primary objective of this project which is to establish a causal relationship between PM exposure and asthma morbidity and to determine the mechanisms by which exposure enhances asthma morbidity. To date, the investigators have determined that a single (0.5 mg/mouse) intratracheal dose of particulate matter collected in urban Baltimore induces significant increases in airway hyperresponsiveness which are sustained over a 7 day period and return to control levels at 14 days. The increase in AHR was preceded by dramafic increases in BAL granulocytes particularly, eosinophils. These physiological changes were associated with an early Th2 cytokine pattern (IL-5, IL- 1 3, eotaxin), which shifted toward a Th1 pattern as AHR and granulocytes returned to normal levels. When the effects of AUB 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, they found that the active components of AUB are not water-soluble, but remain particle-bound. They 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.

Since the investigators have recently identified complement as a susceptibility gene for asthma in a murine model, they evaluated its role in PM-induced AHR. The responses to PM exposure were compared in complement factor 3 (C3) deficient mice and their wildtype controls. Interestingly, C3 deficient mice did not develop AHR, while the wildtype mice developed significant AHR in response to particulate exposure. Immunostaining of lung sections with a fluoresecently labelled 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 a follow-up study to define the cellular source of complement following AUB exposure we have shown that the complement is definitively produced locally in the lung as the message for C3 is upregulated in the airway epithelium. Furthermore, we demonstrate in human bronchial epithelial cells that when stimulated with the Th2 cytokine, IL-1 3, airway epithelial cells produce both IL-1 3 message and protein. Studies are underway to determine whether particulate matter directly stimulates C3 or whether additional signals are required.

Future Activities:

Investigators plans over the next six months include further study of the role of complement in PM-induced allergic airway responses. They plan to determine whether particulate matter directly stimulates C3 or whether it occurs via indirect mechanisms. Once this is established, they will proceed to determine the molecular mechanisms by which PM induces C3.

Supplemental Keywords:

Allergens, Asthma, Biochemistry, Children's Health, Disease and Cumulative Effects, Ecological Risk Assessment, Epidemiology, Human Health Risk Assessment, asthma morbidity, particulate matter exposure, allergic airway responses, Maryland, Baltimore., Health, RFA, Scientific Discipline, Air, Water, Susceptibility/Sensitive Population/Genetic Susceptibility, Health Risk Assessment, Mercury, Risk Assessments, particulate matter, Biology, genetic susceptability, Environmental Chemistry, Allergens/Asthma, Children's Health, Toxicology, cytokines, childhood respiratory disease, disease, health effects, Human Health Risk Assessment, community based, air quality, sensitive populations, asthma, allergen, biological response, human exposure, particulate exposure, children, exposure, particulates, PM, airborne pollutants, environmental health hazard, intervention, toxics, air pollution, community-based intervention, interleukin, human health risk, respiratory problems, inhalation

Progress and Final Reports:

Original Abstract

1998

1999

2000 Progress Report

Final

Main Center Abstract and Reports:

R826724    Center for the Study of 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).
R826724C001 A Randomized, Controlled Trial of Home Exposure Control in Asthma
R826724C002 Mechanisms Of Particulate-Induced Allergic Asthma
R826724C003 Genetic Mechanisms of Susceptibility to Inhaled Pollutants
R826724C004 The Relationship Of Airborne Pollutants And Allergens To Asthma Morbidity