Abstract:
Asthma is a heterogeneous disease that can be broadly classified into type 2, which is primarily steroid-sensitive and eosinophilic, and non-type 2, which is primarily steroid-resistant and neutrophilic. While the mechanisms leading to the development of molecular-targeted therapies for type 2 asthma are being elucidated, much remains to be learned about non-type 2 asthma. To investigate the role of oxidative stress in refractory allergic airway inflammation, we compared asthma models generated by immunizing wild-type and nuclear factor erythroid-2-related factor 2 (Nrf2)-deficient mice with the house dust mite antigen. Both asthma models had similar levels of airway inflammation and hyperresponsiveness, but the Nrf2-deficient mice had increased oxidative stress and exacerbated neutrophilic airway inflammation compared with the wild-type mice. Type 2 cytokines and the expression of GATA3, a transcription factor that is important for Th2 cell differentiation, had decreased in Nrf2-deficient mice compared with the wild-type mice, whereas helper T (Th) 17 cytokines and the expression of RORγt, which is important for Th17 cell differentiation, had increased. Furthermore, the neutrophilic airway inflammation caused by Nrf2 deficiency was ameliorated by interleukin (IL)-17 neutralization. We have concluded that the disruption of the Nrf2-mediated antioxidant defense system contributed to the induction of Th17 differentiation and exacerbated allergic neutrophilic airway inflammation.
摘要:
哮喘是一种异质性疾病,可大致分为2型,主要是类固醇敏感和嗜酸性粒细胞,和非2型,主要是类固醇抗性和嗜中性粒细胞。虽然导致2型哮喘分子靶向疗法发展的机制正在阐明,关于非2型哮喘还有很多需要了解.探讨氧化应激在难治性过敏性气道炎症中的作用,我们比较了通过免疫野生型和核因子红系-2相关因子2(Nrf2)缺陷小鼠与屋尘螨抗原产生的哮喘模型.两种哮喘模型的气道炎症和高反应性水平相似,但与野生型小鼠相比,Nrf2缺陷小鼠的氧化应激增加,中性粒细胞气道炎症加剧.2型细胞因子和对Th2细胞分化重要的转录因子GATA3的表达,与野生型小鼠相比,Nrf2缺陷小鼠的Nrf2下降,而辅助性T(Th)17细胞因子和RORγt的表达,这对Th17细胞分化很重要,增加了。此外,白细胞介素(IL)-17中和可改善Nrf2缺乏引起的中性粒细胞气道炎症。我们得出的结论是,Nrf2介导的抗氧化防御系统的破坏有助于诱导Th17分化并加剧过敏性中性粒细胞气道炎症。