Transient Receptor Potential Ion Channels Mediate Adherens Junctions Dysfunction in a Toluene Diisocyanate-Induced Murine Asthma Model
Transient Receptor Potential Ion Channels Mediate Adherens Junctions Dysfunction in a Toluene Diisocyanate-Induced Murine Asthma Model
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瞬态受体电位离子通道介导甲苯二异氰酸酯诱导的小鼠哮喘模型中的粘附连接功能障碍
DOI：
10.1093/toxsci/kfy285
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发表时间：
2019
影响因子：
3.8
通讯作者：
Qingling Zhang
中科院分区：
文献类型：
--
作者：
Lihong Yao;Shuyu Chen;Haixiong Tang;Peikai Huang;Shushan Wei;Zhenyu Liang;Xin Chen;Hongyu Yang;Ailin Tao;Rongchang Chen;Qingling Zhang
上皮细胞-细胞连接的破坏对于哮喘呼吸道炎症的启动和持续是必不可少的。我们之前曾报道甲苯二异氰酸酯(TDI)诱导的职业性哮喘模型上皮屏障完整性受损。本研究旨在探讨瞬时受体电位香草素4(TRPV4)和瞬时受体电位锚蛋白1(TRPA1)在TDI诱导的哮喘黏附连接功能障碍中的作用。用TDI致敏和激发小鼠建立化学致敏哮喘模型。分别给予TRPV4型糖原合成酶激酶(GSK)2193874、5、10 mg/kg和TRPA1(HC030031、10、20 mg/kg)选择性阻断剂。免疫组织化学显示TRPV4和TRPA1在肺组织中的表达模式不同。TDI暴露可使TRPV4表达增加，GSK2193874可抑制TRPV4的表达，而单独使用TDI或TDI与HC030031联用均可引起肺组织TRPA1表达的变化。阻断TRPV4或TRPA1均可剂量依赖性地抑制TDI诱导的气道高反应性、中性粒细胞和嗜酸性粒细胞增多以及Th2反应。同时，吸入甲苯二异氰酸酯后，E-钙粘素和β-连环蛋白的膜水平显著降低，GSK2193874或HC030031可抑制这一作用。此外，GSK2193874和HC030031还抑制致敏和激发小鼠糖原合成酶3β的丝氨酸磷酸化、β-连环蛋白的酪氨酸磷酸化以及β-连环蛋白的激活和核转运。我们的研究表明，在TDI诱导的哮喘中，TRPV4和TRPA1都在E-钙粘蛋白和β-连环蛋白功能障碍中起重要作用，为哮喘的治疗提供了新的靶点。
Disruption of epithelial cell-cell junctions is essential for the initiation and perpetuation of airway inflammation in asthma. We’ve previously reported compromised epithelial barrier integrity in a toluene diisocyanate (TDI)-induced occupational asthma model. This study is aimed to explore the role of transient receptor potential vanilloid 4 (TRPV4) and transient receptor potential ankyrin 1 (TRPA1) in the dysfunction of adherens junctions in TDI-induced asthma. Mice were sensitized and challenged with TDI for a chemical-induced asthma model. Selective blockers of TRPV4 glycogen synthase kinase (GSK)2193874, 5 and 10 mg/kg) and TRPA1 (HC030031, 10 and 20 mg/kg) were intraperitoneally given to the mice. Immunohistochemistry revealed different expression pattern of TRPV4 and TRPA1 in lung. TDI exposure increased TRPV4 expression in the airway, which can be suppressed by GSK2193874, while treatment with neither TDI alone nor TDI together with HC030031 led to changes of TRPA1 expression in the lung. Blocking either TRPV4 or TRPA1 blunted TDI-induced airway hyperreactivity, airway neutrophilia and eosinophilia, as well as Th2 responses in a dose-dependent manner. At the same time, membrane levels of E-cadherin and β-catenin were significantly decreased after TDI inhalation, which were inhibited by GSK2193874 or HC030031. Moreover, GSK2193874 and HC030031 also suppressed serine phosphorylation of glycogen synthase kinase 3β, tyrosine phosphorylation of β-catenin, as well as activation and nuclear transport of β-catenin in mice sensitized and challenged with TDI. Our study suggested that both TRPV4 and TRPA1 contribute critically to E-cadherin and β-catenin dysfunction in TDI-induced asthma, proposing novel therapeutic targets for asthma.