An airway epithelial iNOS-DUOX2-thyroid peroxidase metabolome drives Th1/Th2 nitrative stress in human severe asthma.
An airway epithelial iNOS-DUOX2-thyroid peroxidase metabolome drives Th1/Th2 nitrative stress in human severe asthma.
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作者：
严重难治性哮喘与硝化应激增强有关。为了确定人类严重哮喘中高硝化应激的机制，比较了3-硝基酪氨酸（3 NT）与Th 1和Th 2细胞因子表达。在严重哮喘中，高3 NT水平与高IFN-γ和低IL-13表达相关，这两者都被报道增加人气道上皮细胞（HAEC）中的诱导型一氧化氮合酶（iNOS）。我们发现IL-13和IFN-γ协同增强iNOS、亚硝酸盐和3 NT，对应于增加的H2 O2。过氧化氢酶抑制，而超氧化物歧化酶增强3 NT的形成，支持H2 O2的关键作用，但不是过氧亚硝酸根，在3 NT的产生。双氧化酶-2（DUOX 2）是H2 O2形成的核心，也被IL-13和IFN-γ协同诱导。亚硝酸盐和H2 O2对二氧化氮自由基（NO2·）的催化作用需要该上皮细胞系统中的内源性过氧化物酶。甲状腺过氧化物酶（TPO）基因芯片分析鉴定出区别于对照组和重度哮喘HAEC的基因。IFN-γ诱导HAEC中的TPO，siRNA敲低减少硝化酪氨酸残基。重度哮喘患者DUOX 2、TPO和iNOS水平升高，且与3 NT水平相关。因此，一种新的iNOS-DUOX 2-TPO-NO2·代谢组驱动HAEC中的硝化应激，并且可能在严重哮喘中。
Severe refractory asthma is associated with enhanced nitrative stress. To determine the mechanisms for high nitrative stress in human severe asthma, 3-nitrotyrosine (3NT) was compared with Th1 and Th2 cytokine expression. In severe asthma, high 3NT levels were associated with high IFN-γ and low IL-13 expression, both of which have been reported to increase inducible nitric oxide synthase (iNOS) in human airway epithelial cells (HAEC). We found IL-13 and IFN-γ synergistically enhanced iNOS, nitrite and 3NT, corresponding with increased H2O2. Catalase inhibited while superoxide dismutase enhanced 3NT formation, supporting a critical role for H2O2 but not peroxynitrite, in 3NT generation. Dual oxidase-2 (DUOX2), central to H2O2 formation, was also synergistically induced by IL-13 and IFN-γ. The catalysis of nitrite and H2O2 to nitrogen dioxide radical (NO2•) 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 severe asthma from controls. IFN-γ induced TPO in HAEC and siRNA knockdown decreased nitrated tyrosine residues. Ex vivo, DUOX2, TPO and iNOS were higher in severe asthma and correlated with 3NT. Thus a novel iNOS-DUOX2-TPO-NO2• metabolome drives nitrative stress in HAEC and likely in severe asthma.
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影响因子：
3.7
作者：
Filosto S;Khan EM;Tognon E;Becker C;Ashfaq M;Ravid T;Goldkorn T
通讯作者：
Goldkorn T
影响因子：
15.9
作者：
Guo, FH;Uetani, K;Erzurum, SC
通讯作者：
Erzurum, SC
影响因子：
6.1
作者：
Chu, H. W.;Balzar, S.;Wenzel, S. E.
通讯作者：
Wenzel, S. E.
影响因子：
4.8
作者：
Geiszt, M;Witta, J;Leto, TL
通讯作者：
Leto, TL
DOI：
10.1164/ajrccm.158.4.9710091
发表时间：
1998-10-01
影响因子：
24.7
作者：
Horv치th, I;Donnelly, LE;Barnes, PJ
通讯作者：
Barnes, PJ