Severe asthma in children is a complex disorder characterized by persistent airway inflammation, ongoing symptoms and extreme morbidity despite treatment with high doses of inhaled corticosteroids. While the pathophysiology of severe asthma is poorly understood, affected children have profound airway "oxidant stress" associated with disturbances in the oxidizing and reducing ("redox") environment. While the clinical ramifications of this oxidant stress are unclear, these disturbances cannot be benign. This study is designed to answer the important clinical question whether corticosteroid sensitivity is altered in children with severe asthma. This study will further determine how airway redox disturbances regulate the response to corticosteroids in children with severe asthma. The hypothesis is that airway redox disturbances inhibit corticosteroid sensitivity through oxidation of the glucocorticoid receptor. To test this hypothesis, the intramuscular corticosteroid, triamcinolone, will be administered to children with severe asthma from the metropolitan Atlanta area who remain symptomatic despite treatment with high doses of inhaled corticosteroids. Corticosteroid insensitivity will be defined as <15% improvement in the forced expiratory volume in one second 4 weeks after triamcinolone administration.
The specific aims of this project are: 1) to determine the clinical pattern and prevalence of corticosteroid insensitivity;2) to determine whether altered airway redox status predicts corticosteroid insensitivity;and 3) to determine whether oxidation of the glucocorticoid receptor is a mechanism of corticosteroid insensitivity in children with severe asthma. The studies presented here will provide critically-needed data to advance the field of severe asthma in children. Although corticosteroids are the cornerstone of asthma treatment, there is very little evidence supporting the use of high doses of corticosteroids in children with severe asthma. New knowledge derived from these aims will demonstrate for the first time whether corticosteroid insensitivity is a true feature of severe asthma in children and whether airway redox disturbances account for this phenomenon. The long-term goal of this research is to utilize these data to develop novel antioxidant interventions to reverse corticosteroid insensitivity in children with severe asthma. The data generated here may therefore improve clinical outcomes in this highly challenging group of children with severe asthma for whom there are very few therapeutic alternatives.

Public Health Relevance

Children with severe asthma have ongoing symptoms and may not respond appropriately to corticosteroid therapy. The purpose of this study is to understand whether corticosteroid insensitivity is a feature of severe asthma in children and whether oxidant stress regulates the response to corticosteroids in these children.

Agency
National Institute of Health (NIH)
Institute
National Institute of Nursing Research (NINR)
Type
Research Project (R01)
Project #
5R01NR012021-04
Application #
8477080
Study Section
Nursing Science: Children and Families Study Section (NSCF)
Program Officer
Huss, Karen
Project Start
2010-06-09
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2013
Total Cost
$363,677
Indirect Cost
$129,047
Name
Emory University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Fitzpatrick, Anne M; Park, Youngja; Brown, Lou Ann S et al. (2014) Children with severe asthma have unique oxidative stress-associated metabolomic profiles. J Allergy Clin Immunol 133:258-61.e1-8
Fitzpatrick, Anne M; Park, Youngja; Brown, Lou Ann et al. (2014) Reply: To PMID 24369802. J Allergy Clin Immunol 133:1499-500
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Fitzpatrick, Anne M; Jones, Dean P; Brown, Lou Ann S (2012) Glutathione redox control of asthma: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal 17:375-408
Fitzpatrick, Anne M; Baena-Cagnani, Carlos E; Bacharier, Leonard B (2012) Severe asthma in childhood: recent advances in phenotyping and pathogenesis. Curr Opin Allergy Clin Immunol 12:193-201
Brown, Sheena D; Baxter, Katherine M; Stephenson, Susan T et al. (2012) Airway TGF-?1 and oxidant stress in children with severe asthma: association with airflow limitation. J Allergy Clin Immunol 129:388-96, 396.e1-8
Sorkness, Ronald L; Teague, W Gerald; Penugonda, Madhuri et al. (2011) Sex dependence of airflow limitation and air trapping in children with severe asthma. J Allergy Clin Immunol 127:1073-4
Fitzpatrick, Anne M; Teague, W Gerald; National Institutes of Health/National Heart, Lung, and Blood Institute's Severe Asthma Research Program (2011) Progressive airflow limitation is a feature of children with severe asthma. J Allergy Clin Immunol 127:282-4
Fitzpatrick, Anne M; Stephenson, Susan T; Hadley, Graham R et al. (2011) Thiol redox disturbances in children with severe asthma are associated with posttranslational modification of the transcription factor nuclear factor (erythroid-derived 2)-like 2. J Allergy Clin Immunol 127:1604-11