Glutathione Oxidation Is Associated With Airway Macrophage Functional Impairment in Children With Severe Asthma

Abstract

Airway cellular dysfunction is a differentiating feature of severe asthma in children that may be related to an imbalance of the antioxidant, glutathione (GSH). We hypothesized that oxidation of GSH to glutathione disulfide (GSSG) in the epithelial lining fluid (ELF) of children with severe asthma would contribute to altered airway macrophage (AM) GSH homeostasis and AM cellular dysfunction. Bronchoalveolar lavage (BAL) was performed in 64 asthmatic children (severe asthma, n = 43). GSH, GSSG, markers of lipid peroxidation and DNA oxidation, and IL-8 were quantified in the BAL supernatant. GSH, GSSG, activities of histone deacetylase (HDAC) and histone acetyltransferase, apoptosis, and phagocytosis were assessed in isolated AMs. Children with severe asthma had increased GSSG, lipid peroxidation, byproducts of DNA oxidation, and inflammation in the ELF. This imbalance of GSH homeostasis was also noted intracellularly within the AMs and was associated with decreased HDAC activities, increased apoptosis, and impaired phagocytosis. In vitro GSH supplementation inhibited apoptosis and rescued phagocytosis in children with severe asthma. Severe asthma in children is characterized by altered airway and intracellular AM GSH homeostasis that translates to impaired AM function. Interventions to restore airway GSH homeostasis may be warranted in children with severe asthma.

Anti-malarial drug artesunate ameliorates oxidative lung damage in experimental allergic asthma

“…On the other hand, 8-OHdG is an indicator of oxidative DNA damage and is formed when reactive OH attacks deoxyguanosine nucleotides in DNA [18]. Increased 8-OHdG levels have been observed in severe asthmatics [42]. In this study, we observed a consistent suppression of these oxidative damage biomarkers by artesunate in the inflamed lungs, suggesting that artesunate could markedly lessen reactive oxygen and nitrogen species in the lungs and prevent oxidant-induced lung damage.…”

Hyperoxidized peroxiredoxins in peripheral blood mononuclear cells of asthma patients is associated with asthma severity

“…Similarly, in a recent study, children with severe asthma had increased concentrations of glutathione disulfide (GSSG), a product of oxidized glutathione, compared with mild asthmatics (Fitzpatrick et al, 2011). Furthermore, this imbalance in GSH homeostasis was associated with decreased HDAC activity which is critically linked to steroid resistance, a characteristic feature of severe asthma.…”

Нозоспецифічні Особливості Редокс-Процесів При Бронхіальній Астмі Та Хронічній Обструктивній Хворобі Легень

“…Считают, что повышение концентрации GSSG, наблюдаемое при БА, обусловлено увели-чением активности гистоновых ацетилтрансфераз, подавлением активности гистоновых деацетилаз в клетках респираторного тракта. Повышение кон-центрации GSSG сопровождается усилением про-дукции провоспалительных цитокинов, в том числе и IL-8/CXCL8, рекрутирующего нейтрофилы [44], и развитием макрофагальной дисфункции [24]. Де-фицит GSH обусловливает ингибирование продук-ции Th 1 -ассоциированных цитокинов и активацию их синтеза [51], в то время как увеличение содержа-ния GSH в клетках респираторного тракта приводит к снижению содержания IL-4, -5, -10, эотаксина, CCL5/RANTES в жидкости бронхоальвеолярного лаважа и усилению продукции IL-12, IFN-γ [25].…”