State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Global Health Institute, Nicholas School of the Environment, Duke University, Durham, NC, USA.
FASEB J. 2021 May;35(5):e21428. doi: 10.1096/fj.201902627R.
This study was conducted to investigate whether a transient receptor potential ankyrin 1 (TRPA1) antagonist (HC-030031) can reduce airway inflammation and hyperresponsiveness in a murine allergic rhinitis (AR) model. BALB/c mice were sensitized and challenged by ovalbumin (OVA) to induce AR. HC-030031 or vehicle was administrated to mice via intraperitoneal injection prior to OVA challenges. Nose-scratching events, histopathologic alterations of the airways, and bronchial hyperresponsiveness (BHR) were assessed. Differential cells and proinflammatory cytokines in the nasal lavage (NAL) and bronchoalveolar lavage (BAL) fluid were measured. Expressions of TRPA1 in nasal mucosa were examined by immunohistochemistry. TRPA1-expressing vagal neurons were labeled by immunofluorescent staining. HC-030031-treated AR mice had markedly reduced type-2 inflammation in nasal mucosa and ameliorated-nose-scratching events than AR mice received vehicle. HC-030031 treatment also dramatically reduced leucocyte numbers and IL-8 level in the BAL fluid, inhibited lower airway remodeling and fibrosis, and nearly abolished BHR. HC-0300031 treatment significantly inhibited the upregulated number of TRPA1 expressing nasal epithelial cells and TRPA1 expressing sensory neurons, leading to downregulation of SP in both upper and lower airways. Targeting TRPA1 may represent a promising strategy for treating AR and AR-related asthma.
本研究旨在探讨瞬时受体电位锚蛋白 1（TRPA1）拮抗剂（HC-030031）是否可以减轻变应性鼻炎（AR）小鼠模型中的气道炎症和高反应性。BALB/c 小鼠通过卵清蛋白（OVA）致敏和激发来诱导 AR。在 OVA 激发前，通过腹腔注射将 HC-030031 或载体给予小鼠。评估鼻搔抓事件、气道的组织病理学改变和支气管高反应性（BHR）。测量鼻洗液（NAL）和支气管肺泡灌洗液（BAL）中的差异细胞和促炎细胞因子。通过免疫组织化学检查鼻黏膜中 TRPA1 的表达。通过免疫荧光染色标记表达 TRPA1 的迷走神经神经元。与接受载体的 AR 小鼠相比，HC-030031 治疗的 AR 小鼠的鼻黏膜 2 型炎症明显减轻，鼻搔抓事件减少。HC-030031 治疗还显著降低了 BAL 液中的白细胞数量和 IL-8 水平，抑制了下气道重塑和纤维化，并几乎消除了 BHR。HC-0300031 治疗显著抑制了鼻上皮细胞中上调的 TRPA1 表达和感觉神经元中表达的 TRPA1 的数量，导致上、下气道中 SP 的下调。靶向 TRPA1 可能是治疗 AR 和 AR 相关哮喘的一种有前途的策略。
