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Author Notes:

Correspondence: Anne M. Fitzpatrick, 2015 Uppergate Drive, Atlanta, GA, 30322; Email: anne.fitzpatrick@emory.edu; Phone: 404-727-9112; Fax: 404-712-0920

Authors' Contributions: First two authors contributed equally to the manuscript.

AMF is the Principal Investigator, oversaw all aspects of the research, and wrote the manuscript.

STS, GH, and LB performed data analysis and interpretation.

MP, DS, JH, DPJ, and LASB were involved in the conception, hypothesis delineation, and design of the study.

Acknowledgments: The authors would like to acknowledge Karen DeMuth, Denise Whitlock, Shanae Wakefield, Christine Spainhour, Michelle Popler, and Emily Morrison for their assistance with subject recruitment and characterization.

Subject:

Research Funding:

Funded by NIH RO1 NR012021 and supported in part by PHS Grant UL1RR025008 from the Clinical and Translational Science Award program, National Institutes of Health, National Center for Research Resources

Keywords:

  • Severe asthma
  • Oxidative stress
  • Inflammation
  • Glutathione
  • Cysteine
  • Nuclear factor (erythroid-derived 2)-like 2 (Nrf2)

Thiol redox disturbances in children with severe asthma are associated with post-translational modification of the transcription factor, Nrf2

Tools:

Journal Title:

Journal of Allergy and Clinical Immunology: In Practice

Volume:

Volume 127, Number 6

Publisher:

, Pages 1604-1611

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Rationale Airway thiol redox disturbances, including depletion of the antioxidant, glutathione (GSH), are differentiating features of severe asthma in children. Objectives Given the role of the transcription factor, Nrf2, in maintaining GSH homeostasis and antioxidant defense, we quantified expression and activity of Nrf2 and its downstream targets in the airways and systemic circulation of asthmatic children. We hypothesized that Nrf2 activation and function would be impaired in severe asthma, resulting in depletion of thiol pools and insufficient GSH synthesis and conjugation. Methods Peripheral blood mononuclear cells (PBMCs) and airway lavage cells were collected from children 6–17 years with severe (n=51) and mild-to-moderate asthma (n=38). The thiols GSH and cysteine (CyS) were quantified and expression and activity of Nrf2 and its downstream targets were assessed. Results Children with severe asthma had greater oxidation and lower concentrations of GSH and Cys in the plasma and airway lavage. Although Nrf2 mRNA and protein increased in severe asthma as a function of increased thiol oxidation, the Nrf2 expressed was highly dysfunctional. Nrf2 activation and downstream targets of Nrf2 binding, including GSH-dependent enzymes, were not different between groups. The duration of asthma was a key factor associated with Nrf2 dysfunction in severe asthma. Conclusions Children with severe asthma have a global disruption of thiol redox signaling and control in both the airways and systemic circulation that is associated with post-translational modification of Nrf2. We conclude that the Nrf2 pathway is disrupted in severe asthma as a function of chronic oxidative stress, which ultimately inhibits GSH synthesis and antioxidant defense.

Copyright information:

© 2011 American Academy of Allergy, Asthma and Immunology. Published by Mosby, Inc. All rights reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported License (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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