Inhibition of TRPA1 reduces airway inflammation and hyperresponsiveness in mice with allergic rhinitis
Inhibition of TRPA1 reduces airway inflammation and hyperresponsiveness in mice with allergic rhinitis
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DOI：
10.1096/fj.201902627r
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发表时间：
2021-05-01
期刊：
影响因子：
4.8
通讯作者：
Xie, Jiaxing
中科院分区：
文献类型：
--
作者：
Fang, Zhangfu;Yi, Fang;Xie, Jiaxing
本研究旨在研究瞬时受体电位锚蛋白1（TRPA 1）拮抗剂（HC-030031）是否可以减轻小鼠变应性鼻炎（AR）模型中的气道炎症和高反应性。用卵清蛋白（OVA）致敏BALB/c小鼠，激发AR。在OVA激发前，通过腹膜内注射向小鼠给予HC-030031或溶剂。对鼻搔事件、气道组织病理学改变和支气管高反应性（BHR）进行评估。检测鼻灌洗液（NAL）和支气管肺泡灌洗液（BAL）中的分化细胞和促炎细胞因子。免疫组化法检测鼻黏膜TRPA 1的表达。通过免疫荧光染色标记表达TRPA 1的迷走神经元。与接受溶剂的AR小鼠相比，HC-030031给药AR小鼠的鼻粘膜2型炎症显著减少，鼻抓挠事件改善。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处理显著抑制了表达TRPA 1的鼻上皮细胞和表达TRPA 1的感觉神经元的上调数量，导致上呼吸道和下呼吸道中SP的下调。靶向TRPA 1可能是治疗AR和AR相关哮喘的一种有前途的策略。
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.