Low temperature reduces occludin expression in bronchial epithelial cells: Implications in cold-induced asthma.
Low temperature reduces occludin expression in bronchial epithelial cells: Implications in cold-induced asthma.
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DOI：
10.1016/j.molimm.2023.03.018
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发表时间：
2023-04
影响因子：
3.6
通讯作者：
Tingyang Zhou;W. Liao;Xiaofen Wang;Yi-yun Wang;Pingchang Yang;L. Zuo;Xiaowen Zhang
中科院分区：
文献类型：
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作者：
Tingyang Zhou;W. Liao;Xiaofen Wang;Yi-yun Wang;Pingchang Yang;L. Zuo;Xiaowen Zhang
背景寒冷暴露是诱发哮喘发作的常见因素。然而，其内在机制尚未完全阐明。我们的目的是调查的假设，低温降低occludin的表达和妥协的上皮屏障功能，在气道，这反过来又导致哮喘acceleration.MethodsWe检查occludin表达在人支气管上皮细胞系（Beas-2B）细胞暴露于29 °C或37 °C。在冷处理前给予以下药物：MG 132（一种蛋白酶体抑制剂）、放线菌酮（一种蛋白质合成抑制剂）、HC-067047 + GSK 2193874（瞬时受体电位香草素4 [TRPV 4]拮抗剂）或C4-神经酰胺（一种糖皮质激素诱导激酶[SGK 1]激活剂）。将siNedd 4 -2转染到Beas-2B细胞中，以研究Nedd 4 -2在介导冷诱导的闭合蛋白不稳定性中的作用。在动物实验中，我们用30 °C的热中性温度或冷暴露（10 °C，6小时/天）治疗卵清蛋白（OVA）诱导的哮喘小鼠2周。在冷处理期间给予GSK 2193874或C4-神经酰胺。Occludin表达的肺，肺的通透性，血清IgE水平，和肺部inflammations.ResultsLow温度处理（29 °C）显着降低occludin在Beas-2B细胞的表达，从1至9小时，这是抢救治疗后与MG 132，HC-067047加GSK 2193874，C4-神经酰胺，或Nedd 4 -2敲低。低温通过SGK 1/Nedd 4 -2依赖的蛋白水解作用影响occludin的稳定性。体内数据显示，冷暴露损害了气道上皮屏障功能，降低了occludin的表达，并加剧了肺部炎症，结论我们发现了一种潜在的冷诱导哮喘急性发作的机制，涉及Nedd 4 -2-介导的occludin蛋白水解和气道上皮屏障破坏。
BackgroundCold exposure is a common factor to trigger asthma attacks. However, the underlying mechanism has not been thoroughly elucidated. We aimed to investigate the hypothesis that low temperature reduces occludin expression and compromises epithelial barrier function in airways, which in turn, results in asthma exacerbation.MethodsWe examined occludin expression in human bronchial epithelial cell line (Beas-2B) cells exposed to either 29 °C or 37 °C. The following drugs were administered prior to cold treatment: MG132 (a proteasome inhibitor), cycloheximide (a protein synthesis inhibitor), HC-067047 plus GSK2193874 (transient receptor potential vanilloid 4 [TRPV4] antagonists), or C4-ceramide (a glucocorticoid-inducible kinase [SGK1] activator). siNedd4–2 was transfected into Beas-2B cells to investigate the role that Nedd4–2 plays in mediating occludin instability induced by cold. In animal experiments, we treated ovalbumin (OVA)-induced asthmatic mice with a thermoneutral temperature of 30 °C or cold exposure (10 °C, 6 h/day) for 2 weeks. GSK2193874 or C4-ceramide was administered during the cold treatment. Occludin expression of the lung, pulmonary permeability, serum IgE levels, and lung inflammation were assessed.ResultsLow temperature treatment (29 °C) significantly reduced the expression of occludin in Beas-2B cells from 1 to 9 h, which was rescued upon treatment with MG132, HC-067047 plus GSK2193874, C4-ceramide, or Nedd4–2 knockdown. Low temperatures affected occludin stability through SGK1/Nedd4–2-dependent proteolysis.In vivomice data revealed that cold exposure compromised the airway epithelial barrier function, decreased occludin expression, and exacerbated lung inflammation, which was attenuated by the GSK2193874 or C4-ceramide injection.ConclusionWe identified a potential mechanism underlying cold-induced asthma exacerbation involving Nedd4–2-mediated occludin proteolysis and airway epithelial barrier disruption.