An airway epithelial iNOS–DUOX2–thyroid peroxidase metabolome drives Th1/Th2 nitrative stress in human severe asthma
Open accessAbstract
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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Both COX-1 and COX-2 have been related to endothelial dysfunction.
“Two isoforms are expressed in mammals: COX-1 and COX-2, and both of them have been related to endothelial dysfunction (981, 982).”
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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
- ORCID
- Venue
- Mucosal Immunology
- Publisher
- Elsevier BV
- Published
- 2014-09
- Volume
- 7
- Issue
- 5
- Pages
- 1175-1185
- ISSN
- 1933-0219 (ISSN-L)
- PMC
- PMC4130801
- 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
- bronze
- doi.org
- Licence
- 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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