Johns Hopkins Department of Otolaryngology-Head and Neck Surgery, Baltimore, MD.
Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
Int Forum Allergy Rhinol. 2019 Jan;9(1):114-119. doi: 10.1002/alr.22222. Epub 2018 Oct 3.
Oxidative stress exacerbates lower airway diseases including asthma and chronic obstructive pulmonary disease (COPD); however, its role in upper airway (sinonasal) chronic inflammatory disorders is less clear. Nuclear erythroid 2 p45-related factor (Nrf2) is an endogenous mechanism that upon activation invokes an antioxidant response pathway via nuclear translocation and upregulation of cytoprotective genes. We sought to determine whether deletion of Nrf2 enhances susceptibility to allergic sinonasal inflammation in vivo.
Nrf2 mice were subjected to the ovalbumin (Ova)-induced murine model of rhinosinusitis and indices of sinonasal inflammation and epithelial barrier dysfunction were assessed.
We show that deletion of Nrf2 results in enhances indices of allergen-induced sinonasal inflammation including aggravated eosinophil accumulation and goblet cell hyperplasia. An exaggerated increase in epithelial derived inflammatory cytokines including interleukin 33 (IL-33) and thymic stromal lymphopoietin (TSLP) was observed in the nasal lavage fluid and sinonasal mucosal tissue of Nrf2 mice. Furthermore, Nrf2 mice showed heightened Ova-induced barrier dysfunction as measured by serum albumin accumulation in nasal lavage fluid of mice.
These data show that the endogenous Nrf2 pathway limits Ova-induced sinonasal inflammation, epithelial derived inflammatory cytokine production, and epithelial barrier dysfunction in vivo and identify a potential therapeutic target in the management of allergic sinonasal inflammatory disorders. This is the first study to our knowledge which shows that Nrf2 regulates allergic inflammation in the sinonasal cavity in vivo.
氧化应激会加重下呼吸道疾病，包括哮喘和慢性阻塞性肺疾病（COPD）；然而，其在上呼吸道（鼻-鼻窦）慢性炎症性疾病中的作用尚不清楚。核红细胞 2 p45 相关因子（Nrf2）是一种内源性机制，其通过核转位和细胞保护基因的上调来激活抗氧化反应途径。我们试图确定 Nrf2 的缺失是否会增加体内对变应性鼻-鼻窦炎症的易感性。
Nrf2 小鼠被用于卵清蛋白（Ova）诱导的鼻-鼻窦炎模型，评估鼻-鼻窦炎症和上皮屏障功能障碍的指标。
我们表明，Nrf2 的缺失导致过敏原诱导的鼻-鼻窦炎症的指标增强，包括嗜酸性粒细胞积聚和杯状细胞增生加剧。在 Nrf2 小鼠的鼻洗液和鼻-鼻窦黏膜组织中观察到上皮衍生的炎症细胞因子（包括白细胞介素 33（IL-33）和胸腺基质淋巴生成素（TSLP））的过度增加。此外，Nrf2 小鼠表现出 Ova 诱导的屏障功能障碍加剧，表现为小鼠鼻洗液中血清白蛋白的积聚增加。
这些数据表明，内源性 Nrf2 途径限制了 Ova 诱导的鼻-鼻窦炎症、上皮衍生的炎症细胞因子产生和上皮屏障功能障碍，为过敏性鼻-鼻窦炎症性疾病的治疗提供了潜在的靶点。这是我们所知的首次表明 Nrf2 调节体内鼻-鼻窦腔过敏炎症的研究。
