Thiol redox disturbances in children with severe asthma are associated with posttranslational modification of the transcription factor nuclear factor (erythroid-derived 2)–like 2

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.

Blood glutathione redox status and global methylation of peripheral blood mononuclear cell DNA in Bangladeshi adults

“…16 Although some studies have used plasma GSH E h as a marker of intracellular redox, 44,45 we did not observe significant correlations of Hcys or SAH with plasma GSH E h , which suggests that whole blood GSH E h might be a better indicator of the intracellular redox environment, at least within blood cells. However, an oxidized plasma GSH E h is thought to reflect oxidative stress in other tissues 46 or systemic oxidative stress 47 and is observed in aging, 48 obesity 49 and disease states such as asthma 50 and heart disease. 51 Indeed, we found that plasma GSH E h , but not blood GSH E h , was positively correlated with age (Spearman r = 0.14, p = 0.01) and BMI (Spearman r = 0.11, p = 0.05).…”

Role of Transcription Factors in the Pathogenesis of Asthma and COPD

“…NRF2 is a redox-sensitive basic leucine zipper transcription factor whose expression was initially reported to be reduced in the lungs following allergen exposure in mice and NRF2 knockout mice displayed enhanced allergen-driven airway infl ammation and hyperresponsiveness post ovalbumin exposure (Rangasamy et al, 2005). Altered oxidant responses have been seen particularly in severe asthma and this has been related to post-translational modifi cations of NRF2 which altered its ability to switch on anti-oxidant genes (Fitzpatrick et al, 2011). NRF2 activation is also involved in infl ammatory gene expression following bacterial lipopolysaccharide (LPS)-stimulation of airway epithelial cells and macrophages , controls eotaxin/CCL11 expression and release from airway fi broblasts (Fourtounis et al, 2012) and proliferation of airway smooth cells (Michaeloudes et al, 2011).…”

Relationship between air pollution, NFE2L2 gene polymorphisms and childhood asthma in a Hungarian population

“…Earlier, Fitzpatrick et al (2011) showed that children with severe asthma have elevated NFE2L2 mRNA and protein levels as a function of increased thiol oxidation, but this increase has no effect on the downstream components of the antioxidant pathway, suggesting a posttranslational modification. One of the possible explanations for the NFE2L2 dysfunction and redox disturbances in severe asthma is the presence of single nucleotide polymorphisms in the NFE2L2 promoter.…”