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2002 Progress Report: Chemokines in the Pathogenesis of Asthma (Asthma Chemokines)
EPA Grant Number: R826710C002Subproject: this is subproject number 002 , established and managed by the Center Director under grant R826710
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: Michigan Center for the Environment and Children’s Health
Center Director: Israel, Barbara A.
Title: Chemokines in the Pathogenesis of Asthma (Asthma Chemokines)
Investigators: Israel, Barbara A. , Brown, Randall , Keeler, Gerald J. , Lin, Xihong , Parker, Edith , Philbert, Martin , Remick, Daniel , Robins, Thomas
Institution: University of Michigan - Ann Arbor
EPA Project Officer: Saint, Chris
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)
Research Category: Children's Health , Health Effects
Description:
Objective:Chemokines in the Pathogenesis of Asthma (Core 3)
There have been no changes in the specific objectives. Asthma represents
a serious health problem particularly for inner city children. Recent studies
have identified that many of the asthmatic attacks are triggered by exposure
to cockroaches. It is not exposure to the entire cockroach, but only small
fragments or residue. These small fragments are responsible for the allergic
response and they are called allergens. In the normal allergic, or asthmatic
response, the body reacts to the allergens to start inflammation. This inflammation
is initiated by having the cells of the body produce specific chemicals or
mediators. With asthma, most of the mediators are produced directly in the
lung. While many potential mediators have been examined previously, asthma
still exacts a toll on children and adults. More specific, targeted therapy
has the potential to improve the treatment of asthma by identifying those
mediators directly responsible for the causing disease.
This research project will test the hypothesis that asthma-like pulmonary injury is mediated by the local production of specific mediators, which are called chemokines. Chemokines are small molecular weight proteins which induce the movement and recruitment of inflammatory cells. The chemokines are powerful mediators with long lasting and potent biological activities. The first specific aim is to determine the acute and chronic pulmonary inflammation that develops after direct injection of the chemokines into the lung. The assessment of the injury will include a microscopic analysis of the lung as well as an assessment of the nerves within the airways. The second specific aim is to develop a mouse model of asthma-like pulmonary inflammation in response to cockroach allergens. For this specific aim, a model in mice which is similar to humans will be set up to attempt to decipher the specific mediators that cause the lung injury. This model will be established by locating households with high levels of cockroach allergens and using this material to immunize the mice. The mice will be challenged by exposure to aerosols containing the dust with the cockroach allergens and the pulmonary injury carefully quantitated including an analysis of innervation of the airways. The third specific aim is to investigate the signals responsible for inducing the cells to make the chemokines. This will be done in cells sensitized and then challenged with cockroach allergens. This will focus on reactive oxygen and reactive nitrogen intermediates since they have been demonstrated to increase the synthesis of chemokines.
The last specific aim is to rigorously test the central hypothesis that chemokines are important in causing asthma. This will be tested by blocking the biological activity of the chemokines with specific therapies to inhibit the chemokines and then determining if there is a reduction in the pulmonary inflammation induced by repeated exposures to the cockroach allergens. Successful completion of this project will both delineate the underlying mechanisms of disease and identify potential novel targets for intervention.
Progress Summary:There continues to be progress in the investigations into the novel model of asthma like pulmonary inflammation induced by house dust containing high levels of cockroach allergens. Previous data have been generated from one lot of house dust. Project investigators sought to determine whether the findings could be generalized to house dust collected from other homes. For these investigations, house dust was collected from five different homes and prepared an aqueous extract of the house dust. Within this aqueous extract, allergen levels were measured including the cockroach allergens, dust mite allergens, and dog and cat allergens, and outdoor allergens. Additionally, endotoxin within this extract was determined. Each of the five house dust extracts contained high levels of cockroach allergens as well as endotoxin. These results were not surprising since the dust was collected from the kitchen where there is a higher likelihood of cockroach infestation compared to the bedrooms. Groups of mice were immunized with this aqueous extract and challenged twice. Measurements included airways hyperreactivity, pulmonary inflammatory cell recruitment, pulmonary and plasma chemokine production, and plasma levels of IgE. Each one of the house dust extracts was able to induce significant pulmonary inflammation in the sensitized mice. This pulmonary inflammation consisted of both neutrophilic and eosinophilic infiltration into the airways, increased airways reactivity to inhaled methacholine was also present, and there were elevated plasma levels of both CC chemokines as well as plasma IgE. Ihese results indicate that this model of airways hyperreactivity may be induced by any house dust extract containing high levels of cockroach allergens. These data will be used by the graduate student in the laboratory, Laura McKinley, as a portion of her Ph.D. thesis defense. Additionally, the investigators intend to submit these data for peer reviewed publication.
An important axis exists between the innate and the adaptive immune response in several inflammatory conditions. Neutrophil chemoattractants such as the CXC chemokines are classically considered part of the innate immune response. However, emerging data indicates that neutralization of the CXC chemokines has significant impact upon the adaptive immune response. There are multiple CXC chemokines within the murine inflammatory system, but two of the best characterized are KC and MIP-2. Neutralizing antibodies to both of these chemokines were raised and used to treat mice prior to the onset of the pulmonary inflammation. Results indicated that neutralization of a classically considered portion of the innate response would significantly decrease the adaptive immune response. These results have been presented in abstract form of the 2002 experimental biology meeting which was held in New Orleans, Louisiana. The abstract is listed at the end of this report.
Clinically, glucocorticoids are for only used for the treatment of asthma. These potent immunosuppressants are also used to "break" an acute asthmatic attack. That is, after the onset of inflammation, these compounds may still be effective. Investigators sought to determine whether the novel model of asthma like pulmonary inflammation may be decreased once the inflammatory process is well established by treatment. This will extend the range of the utility of the model, if the mice can be treated in the same manner as human patients, and observed the same improvement. For these experiments, the mice are immunized at the house dust extract and then subjected to 2 pulmonary challenges. Twenty-four hours after the second pulmonary challenge, airways hyperreactivity was measured. A group of mice was treated with dexamethasone, while the control group was treated with the vehicle alone. The dexamethasone was able to significantly reverse the airways hyperreactivity. Additionally, if the mice were pretreated with dexamethasone prior to the pulmonary challenge, there was a significant reduction in the total plasma IgE, airways hyperreactivity, and inflammatory cell recruitment into the lung. These data demonstrate the clinical utility of this novel model.
Please refer to the main center progress report.
Journal Articles:No journal articles submitted with this report: View all 3 publications for this subproject
Supplemental Keywords:Children's health, human health risk, exposure assessment, asthma triggers, chemokines, cockroaches, pulmonary inflammation, animal models. , Air, Scientific Discipline, Health, RFA, Susceptibility/Sensitive Population/Genetic Susceptibility, Toxicology, Biology, indoor air, genetic susceptability, Health Risk Assessment, Children's Health, Environmental Chemistry, Allergens/Asthma, environmental hazard exposures, allergen, health effects, indoor air quality, inhalation, respiratory problems, indoor environment, assessment of exposure, childhood respiratory disease, toxics, cockroaches, home, respiratory, sensitive populations, biological response, mediators, asthma chemokines, airway disease, children, lung, disease, exposure, pulmonary, children's vulnerablity, asthma triggers, allergic response, asthma, Human Health Risk Assessment, airway inflammation
Progress and Final Reports:
1999 Progress Report
2000 Progress Report
Original Abstract
Main Center Abstract and Reports:
R826710 Michigan Center for the Environment and Children’s Health
Subprojects under this Center:
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R826710C001 Indoor and Outdoor Air Contaminant Exposures and Asthma Aggravation Among Children (Asthma Exposure)
R826710C002 Chemokines in the Pathogenesis of Asthma (Asthma Chemokines)
R826710C003 A Community-Based Intervention to Reduce Environmental Triggers for Asthma Among Children (Asthma Intervention)