<br>功能失调的 ErbB2（EGF 受体家族成员）会阻碍哮喘患者气道上皮细胞的修复。,Journal of Allergy and Clinical Immunology

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功能失调的 ErbB2（EGF 受体家族成员）会阻碍哮喘患者气道上皮细胞的修复。
Journal of Allergy and Clinical Immunology ( IF 11.4 ) Pub Date : 2019-01-10 , DOI: 10.1016/j.jaci.2018.11.046
Hideki Inoue ₁ , Takeshi Hattori ₂ , Xiuxia Zhou ₂ , Emily B Etling ₂ , Brian D Modena ₃ , John B Trudeau ₂ , Fernando Holguin ₄ , Sally E Wenzel ₂

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背景遗传和基因组数据越来越多地表明气道上皮对于哮喘发病机制至关重要。上皮生长因子 (EGF) 家族成员在上皮分化、增殖和修复中发挥着重要作用。据报道，成红细胞增多症癌基因 B2 (ErbB2) mRNA（一种 EGF 家族受体）在哮喘患者中的表达较低，但对其功能作用知之甚少。目的我们试图确定哮喘患者新鲜分离的人气道上皮细胞 (HAEC) 中 ErbB2 活性的降低是否与体外伤口闭合受损有关。方法采用气液界面培养和新鲜分离的 HAEC 的体外划伤模型，比较来自健康对照受试者 (HC) 和哮喘患者的 HAEC 与 ErbB2 的关系。结果与 HC 相比，来自哮喘患者的刚刷过的 HAEC 的 ErbB2 激活受损。在体外划痕伤口模型中，与来自健康人的 HAEC 相比，来自哮喘患者的 HAEC 表现出伤口闭合延迟。哮喘患者和 HC 的 HAEC 中，根据受伤后 [3H] 胸苷掺入评估的细胞增殖以及伤口前缘 ErbB2 和细胞周期蛋白 D1 的表达或激活较低。选择性 ErbB2 酪氨酸激酶抑制剂 mubritinib 可损害健康 HAEC 中的伤口闭合并降低细胞周期蛋白 D1 表达，对哮喘患者细胞的影响较小，支持哮喘患者活动的减少。结论这些结果表明 ErbB2 通路的主要缺陷限制了哮喘患者的上皮修复过程。 ErbB2 稳态功能的恢复应被视为新的哮喘治疗目标。

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Dysfunctional ErbB2, an EGF receptor family member, hinders repair of airway epithelial cells from asthmatic patients.

BACKGROUND Genetic and genomic data increasingly point to the airway epithelium as critical to asthma pathogenesis. Epithelial growth factor (EGF) family members play a fundamental role in epithelial differentiation, proliferation, and repair. Although expression of erythroblastosis oncogene B2 (ErbB2) mRNA, an EGF family receptor, was reported to be lower in asthmatic patients, little is understood about its functional role. OBJECTIVE We sought to determine whether decreased ErbB2 activation in freshly isolated human airway epithelial cells (HAECs) from asthmatic patients associated with impaired wound closure in vitro. METHODS An in vitro scratch-wound model of air-liquid interface cultured and freshly isolated HAECs were compared between HAECs from healthy control subjects (HCs) and asthmatic patients in relation to ErbB2. RESULTS Freshly brushed HAECs from asthmatic patients had impaired ErbB2 activation compared with those from HCs. In an in vitro scratch-wound model, HAECs from asthmatic patients showed delayed wound closure compared with HAECs from HCs. Cell proliferation, as assessed based on [3H] thymidine incorporation after wounding, and expression or activation of ErbB2 and cyclin D1 at the leading edge of the wound were lower in HAECs from asthmatic patients and HCs. A selective ErbB2 tyrosine kinase inhibitor, mubritinib, impaired wound closure and decreased cyclin D1 expression in healthy HAECs, with less effect on cells from asthmatic patients, supporting diminished activity in asthmatic patients. CONCLUSION These results implicate a primary defect in the ErbB2 pathway as constraining epithelial repair processes in asthmatic patients. Restoration of homeostatic ErbB2 function should be considered a novel asthma therapeutic target.

更新日期：2019-01-10

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