Cited by 120Asthma and respiratory diseasesRedox biology and oxidative stressNitric Oxide and Endothelin Effects

An airway epithelial iNOS–DUOX2–thyroid peroxidase metabolome drives Th1/Th2 nitrative stress in human severe asthma

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Voraphani, N, Gladwin, M T, Contreras, A U, Kaminski, N, Tedrow, J R, Milosevic, J, Bleecker, E R, Meyers, D A +7 more·2014·Mucosal Immunology

Abstract

Severe refractory asthma is associated with enhanced nitrative stress. To determine the mechanisms for high nitrative stress in human severe asthma (SA), 3-nitrotyrosine (3NT) was compared with Th1 and Th2 cytokine expression. In SA, high 3NT levels were associated with high interferon (IFN)-γ and low interleukin (IL)-13 expression, both of which have been reported to increase inducible nitric oxide synthase (iNOS) in human airway epithelial cells (HAECs). We found that IL-13 and IFN-γ synergistically enhanced iNOS, nitrite, and 3NT, corresponding with increased H(2)O(2). Catalase inhibited whereas superoxide dismutase enhanced 3NT formation, supporting a critical role for H(2)O(2), but not peroxynitrite, in 3NT generation. Dual oxidase-2 (DUOX2), central to H(2)O(2) formation, was also synergistically induced by IL-13 and IFN-γ. The catalysis of nitrite and H(2)O(2) to nitrogen dioxide radical (NO(2)(•)) requires an endogenous peroxidase in this epithelial cell system. Thyroid peroxidase (TPO) was identified by microarray analysis ex vivo as a gene distinguishing HAEC of SA from controls. IFN-γ induced TPO in HAEC and small interfering RNA knockdown decreased nitrated tyrosine residues. Ex vivo, DUOX2, TPO, and iNOS were higher in SA and correlated with 3NT. Thus, a novel iNOS-DUOX2-TPO-NO(2)(•) metabolome drives nitrative stress in HAEC and likely in SA.

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Authors
Voraphani, N., Gladwin, M. T., Contreras, A. U., Kaminski, N., Tedrow, J. R., Milosevic, J., Bleecker, E. R., Meyers, D. A., Ray, A., Ray, P., Erzurum, S. C., Busse, W. W., Zhao, J., Trudeau, J. B., & Wenzel, S. E.
Affiliations
  • Chulalongkorn University (TH)
  • University of Pittsburgh (US)
  • Wake Forest University Health Sciences (US)
  • Cleveland Clinic (US)
  • University of Wisconsin–Madison (US)
Corresponding author
Wenzel, S E
Venue
Mucosal Immunology
Publisher
Elsevier BV
Published
2014-09
Volume
7
Issue
5
Pages
1175-1185
ISSN
1933-0219 (ISSN-L)
OpenAlex
W2059121736
Cited by
119
References
52
Citations by year
2026: 1 · 2025: 8 · 2024: 6 · 2023: 6 · 2022: 10 · 2021: 13 · 2020: 12 · 2019: 9 · 2018: 8 · 2017: 10 · 2016: 16 · 2015: 11 · 2014: 9
FWCI
10.22
Type
journal article
Language
en
Open access
Locations
  • Mucosal Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (UL1TR000005)
  • National Heart, Lung, and Blood Institute (HL69174, RC2HL101487, R01HL069174, U10HL109250, R01HL069116, R01HL069167, R01HL069170, HL-69167, HL69116, HL-69170)
  • National Institute of Allergy and Infectious Diseases (AI67780, R01AI067780, P01AI106684)
  • National Center for Research Resources (UL1RR024153)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Physiology › Asthma and respiratory diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Keywords
severe asthma, nitrative stress, nitrotyrosine, inducible nitric oxide synthase, DUOX2, thyroid peroxidase, airway epithelial cells, Th1/Th2 cytokines, interferon-gamma, IL-13, hydrogen peroxide, nitrite, superoxide dismutase, catalase, peroxynitrite, nitrogen dioxide radical, oxidative stress
MeSH terms
Adult, Asthma, Female, Humans, Interferon-gamma, Iodide Peroxidase, Male, Respiratory System, Severity of Illness Index, Stress, Physiological, Th1 Cells, Th2 Cells, Interleukin-13, Microarray Analysis, Nitric Oxide Synthase Type II, Metabolome, Young Adult

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