It is clear that the disease process known as asthma is on the increase in the United States and other developed countries. This increase in the incidence of asthma is not due to changes in the genetic makeup of the population, but rather a combination of environmental factors. Some of the triggers for asthma have been delineated, as well as the actual molecules that drive the inflammatory response. However, the full spectrum of the inflammatory mediators responsible for the initiation and propagation of asthma have yet to be fully defined. We have established a novel model of murine asthma-like pulmonary inflammation based on house dust from the homes of children with asthma. In this application we will build on this novel model to provide closer documentation of the initiators and propagators of the asthma like response. We will pay particular attention to the mechanisms of how these initiators trigger an asthmatic response. Perhaps of greater importance, we will define the inflammatory molecules upregulated by the environmental triggers with particular emphasis on tumor necrosis factor (TNF). The application will focus on the triumvirate of endotoxin, allergens, and outdoor pollutants both singly and in combination. The first specific aim will look at the role of endotoxin in triggering the asthmatic response.
This specific aim will use a combination of removing endotoxin from the house dust in addition to examining endotoxin tolerant animals. Using more than one approach increases the probability of success, as well as enhances the rigor of the observations. In the second specific aim, we will remove the allergen from the house dust extract. In the third specific aim we will determine the potential for concentrated air particles, which represent outdoor pollutants, to exacerbate the asthmatic response. Additionally, we will determine whether exposure to the concentrated air particles will prime an animal to develop an asthmatic response. For each of these specific aims we will not only determine if inflammation is present, but also define the range of inflammatory mediators. In our last specific aim we will integrate the data from the previous work to decrease the asthmatic response by blocking TNF by multiple modalities. The results from these studies will define the participation of endotoxin, allergens and outdoor pollutants in the pathogenesis of asthma and determine the role of TNF in causing the inflammation. Lay language: This application will examine how house dust causes asthma. It will specifically examine how 2 different components found in the house dust, cockroaches and bacteria, interact with outdoor air pollution to result in pulmonary inflammation. We will also investigate if a new drug approved for the treatment of rheumatoid arthritis will also help prevent asthma. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES013538-04
Application #
7488818
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Nadadur, Srikanth
Project Start
2006-06-15
Project End
2011-08-31
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
4
Fiscal Year
2008
Total Cost
$337,523
Indirect Cost
Name
Boston University
Department
Pathology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
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Natarajan, Sudha; Kim, Jiyoun; Bouchard, Jacqueline et al. (2011) Reducing LPS content in cockroach allergens increases pulmonary cytokine production without increasing inflammation: a randomized laboratory study. BMC Pulm Med 11:12
Kim, Jiyoun; Natarajan, Sudha; Bae, Hyunsu et al. (2011) Herbal medicine treatment reduces inflammation in a murine model of cockroach allergen-induced asthma. Ann Allergy Asthma Immunol 107:154-62
Natarajan, Sudha; Kim, Jiyoun; Remick, Daniel G (2010) Chronic pulmonary LPS tolerance induces selective immunosuppression while maintaining the neutrophilic response. Shock 33:162-9
Vaickus, Louis J; Bouchard, Jacqueline; Kim, Jiyoun et al. (2010) Oral tolerance inhibits pulmonary eosinophilia in a cockroach allergen induced model of asthma: a randomized laboratory study. Respir Res 11:160
Vaickus, Louis J; Bouchard, Jacqueline; Kim, Jiyoun et al. (2010) Assessing pulmonary pathology by detailed examination of respiratory function. Am J Pathol 177:1861-9

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