Abstract：
Impaired airway epithelial barrier and decreased expression of E-cadherin are key features of severe asthma. As a gatekeeper of the mucosa, E-cadherin can be cleaved from the cell surface and released into the apical lumen as a soluble form (sE-cadherin).This study was aimed to investigate the role of sE-cadherin in severe asthma.Induced sputum was obtained from healthy subjects and patients with asthma. Two murine models of severe asthma were established using either TDI (toluene diisocyanate) or OVA (ovalbumin)/CFA (complete Freund\'s adjuvants). The role of sE-cadherin in severe asthma was evaluated by intraperitoneal injection of DECMA-1, a neutralizing antibody against sE-cadherin. Mice or THP-1-derived macrophages were treated with recombinant sE-cadherin to explore the pro-inflammatory mechanism of sE-cadherin.Severe asthma patients had a significantly higher sputum sE-cadherin level than the health subjects with mild to moderate asthma, which were positively correlated with sputum HMGB1 level and glucocorticoid dosage required for daily control. Allergen exposure markedly increased sE-cadherin level in the bronchoalveolar lavage fluid in mice. Treatment of DECMA-1 significantly attenuated allergen-induced airway inflammation and hyperresponsivenes in both models of severe asthma. While exposure to recombinant sE-cadherin dramatically up-regulated VEGF expression in THP-1-derived macrophages, and increased neutophlil and eosinophil infiltration into the airway as well as the release of VEGF and IL-6 in mice, both of which can be suppressed by pharmacological inhibition of ERK signaling.Taken together, our data indicated that sE-cadherin contributed to the airway inflammation of severe asthma in an ERK-depedent pathway.
摘要：
气道上皮屏障受损和E-cadherin表达降低是严重哮喘的关键特征。作为粘膜的看门人，E-钙黏着蛋白可以从细胞表面裂解并作为可溶形式(sE-钙黏着蛋白)释放到顶腔中。本研究旨在探讨sE-cadherin在重症哮喘中的作用。从健康受试者和哮喘患者获得诱导痰。使用TDI（甲苯二异氰酸酯）或OVA（卵清蛋白）/CFA（完全弗氏佐剂）建立了两种严重哮喘的小鼠模型。通过腹膜内注射针对sE-cadherin的中和抗体DECMA-1来评估sE-cadherin在严重哮喘中的作用。用重组sE-cadherin处理小鼠或THP-1来源的巨噬细胞以探索sE-cadherin的促炎机制。重度哮喘患者的痰液sE-cadherin水平明显高于轻度至中度哮喘的健康受试者。其与痰液HMGB1水平和每日控制所需的糖皮质激素剂量呈正相关。过敏原暴露显着增加了小鼠支气管肺泡灌洗液中的sE-cadherin水平。DECMA-1治疗可显着减轻两种严重哮喘模型中过敏原诱导的气道炎症和高反应性。虽然暴露于重组sE-cadherin显著上调THP-1来源巨噬细胞的VEGF表达,和增加的嗜中性粒细胞和嗜酸性粒细胞浸润到气道以及释放的VEGF和IL-6的小鼠，两者都可以通过ERK信号传导的药理学抑制来抑制。一起来看,我们的数据表明,sE-cadherin在ERK-dependent途径中促进了重度哮喘的气道炎症.
