Airway Glutathione Homeostasis is Altered in Children withSevere Asthma: Evidence for Oxidant Stress Public

Abstract

Abstract Airway Glutathione Homeostasis is Altered in Children with Severe Asthma: Evidence for Oxidant Stress By Anne M. Fitzpatrick, Ph.D. Severe asthma in children is a complex disorder characterized by persistent airway inflammation and increased formation of reactive oxygen species. Because glutathione (GSH) is an important antioxidant in the epithelial lining fluid (ELF), we hypothesized that airway GSH homeostasis was altered in children with severe asthma and was characterized by decreased GSH and increased glutathione disulfide (GSSG) concentrations. Bronchoalveolar lavage was obtained from 65 children with severe asthma, including 35 children with baseline airway obstruction evidenced by FEV1 < 80%. Control data was obtained from 6 children with psychogenic (habit) cough or vocal cord dysfunction undergoing diagnostic bronchoscopy and 35 healthy adult controls. GSH, GSSG, and other determinants of airway oxidative stress including glutathione S-transferase (GST), glutathione reductase (GR), glutathione peroxidase (GPx), malondialdehyde (MDA), 8- isoprostane, and hydrogen peroxide (H2O2) were measured in the ELF. The ELF redox potential was calculated from GSH and GSSG using the Nernst equation. Compared to controls, severe asthmatics had lower airway GSH with increased GSSG despite no differences in GST, GR, and GPx activities between groups. This was accompanied by increased MDA, 8-isoprostane, and H2O2 concentrations in the ELF. GSH oxidation was most apparent in severe asthmatics with airway obstruction and was supported by an upward shift in the ELF GSH redox potential. We conclude that children with severe asthma have increased biomarkers of oxidant stress in the ELF which are associated with increased formation of GSSG and a shift in the GSH redox potential toward the more oxidized state.

Table of Contents

TABLE OF CONTENTS

I. Introduction ...................................................................................... 1 II. Background ...................................................................................... 3 III. Methods ........................................................................................... 5 Null hypothesis ....................................................................... 5 Study design ......................................................................... 5 Sample ................................................................................ 5 Outcome variable .................................................................... 6 Predictor variables .................................................................. 6 Procedures ........................................................................... 7 Sample size calculations ........................................................... 10 Statistical analyses .................................................................. 10 IV. Results .......................................................................................... 12 V. Discussion ...................................................................................... 16 VI. References ...................................................................................... 20 VII. Tables ........................................................................................... 28 Table I ............................................................................... 28 Table II ............................................................................... 29 Table III .............................................................................. 30 Table IV .............................................................................. 31 Table V ............................................................................... 32 Table VI .............................................................................. 33 Table VII ............................................................................ 34

Table VIII ........................................................................... 35 Table IX ............................................................................. 36 Table X .............................................................................. 37 Table XI ............................................................................. 38 VIII. Figures .......................................................................................... 39 Figure 1 .............................................................................. 39 Figure 2 ............................................................................... 40 Figure 3 .............................................................................. 41 Figure 4 ............................................................................... 42 Figure 5 .............................................................................. 43 Figure 6 ............................................................................... 44 Figure 7 ............................................................................... 45 Figure 8 .............................................................................. 46 Figure 9 ............................................................................... 47

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School	Laney Graduate School
Department	Clinical Research Curriculum Program
Degree	MS
Submission	Dissertation
Language	English
Research Field	Health Sciences, General
Mot-clé	asthma
Committee Chair / Thesis Advisor	Brown, Lou Ann, Emory University
Committee Members	Boring, John R, Emory University McGowan Jr., John E, Emory University Blumberg, Henry Michael, Emory University

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