Thiol redox disturbances in children with severe asthma are associated with posttranslational modification of the transcription factor nuclear factor (erythroid-derived 2)-like 2
Thiol redox disturbances in children with severe asthma are associated with posttranslational modification of the transcription factor nuclear factor (erythroid-derived 2)-like 2
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DOI：
10.1016/j.jaci.2011.03.031
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发表时间：
2011-06-01
影响因子：
14.2
通讯作者：
Brown, Lou Ann S.
中科院分区：
文献类型：
--
作者：
Fitzpatrick, Anne M.;Stephenson, Susan T.;Brown, Lou Ann S.
背景资料：气道巯基氧化还原紊乱，包括抗氧化剂，谷胱甘肽的消耗，严重asthma in children. Objective. Objective. Given的转录因子核因子（红细胞衍生2）样2（NRF 2）在维持谷胱甘肽稳态和抗氧化防御的作用，我们量化的表达和活性的NRF 2及其下游目标的气道和体循环的儿童哮喘。我们假设，Nrf 2的激活和功能将在严重哮喘受损，导致巯基池和谷胱甘肽的合成和conjugation.Methods不足耗尽：PBMC和气道灌洗液细胞收集6至17岁的儿童严重（n = 51）和轻中度哮喘（n = 38）。巯基谷胱甘肽和半胱氨酸进行了定量，表达和活性的Nrf 2及其下游targets.Results：儿童严重哮喘有更大的氧化和较低浓度的谷胱甘肽和半胱氨酸的血浆和气道灌洗液进行了评估。虽然Nrf 2 mRNA和蛋白质在重度哮喘中作为巯基氧化增加的功能而增加，但Nrf 2表达高度功能失调。Nrf 2激活和Nrf 2结合的下游靶点，包括谷胱甘肽依赖性酶，在组间没有差异。结论：重症哮喘患儿呼吸道和体循环中的巯基氧化还原信号转导和控制受到全面破坏，这与Nrf 2的翻译后修饰有关。我们的结论是，Nrf 2通路在严重哮喘中作为慢性氧化应激的功能被破坏，最终抑制谷胱甘肽合成和抗氧化防御。（J Allergy Clin Immunol 2011;127：1604-11.）
Background: Airway thiol redox disturbances, including depletion of the antioxidant, glutathione, are differentiating features of severe asthma in children.Objectives: Given the role of the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in maintaining glutathione homeostasis and antioxidant defense, we quantified expression and activity of Nrf2 and its downstream targets in the airways and systemic circulation of children with asthma. We hypothesized that Nrf2 activation and function would be impaired in severe asthma, resulting in depletion of thiol pools and insufficient glutathione synthesis and conjugation.Methods: PBMCs and airway lavage cells were collected from children 6 to 17 years with severe (n = 51) and mild-to-moderate asthma (n = 38). The thiols glutathione and cysteine 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 glutathione and cysteine 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 glutathione-dependent enzymes, were not different between groups. The duration of asthma was a key factor associated with Nrf2 dysfunction in severe asthma.Conclusion: 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 posttranslational modification of Nrf2. We conclude that the Nrf2 pathway is disrupted in severe asthma as a function of chronic oxidative stress, which ultimately inhibits glutathione synthesis and antioxidant defense. (J Allergy Clin Immunol 2011;127:1604-11.)