Tang Haixiong, Chen Zemin, Gan Sudan, Guo Yubiao, Yang Changyun, Dong Meihua, Fu Lin, Chen Huifang, Tao Ailin, Li Jing, Li Shiyue, Yao Lihong
Department of Allergy and Clinical Immunology, State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
Guangzhou Medical University, Guangzhou, Guangdong, China.
Am J Respir Cell Mol Biol. 2024 Jul 30. doi: 10.1165/rcmb.2024-0133OC.
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.
气道上皮屏障受损和E-钙黏蛋白表达降低是重度哮喘的关键特征。作为黏膜的守门人，E-钙黏蛋白可从细胞表面裂解并以可溶性形式（sE-钙黏蛋白）释放到顶端管腔中。本研究旨在探讨sE-钙黏蛋白在重度哮喘中的作用。从健康受试者和哮喘患者中获取诱导痰。使用甲苯二异氰酸酯（TDI）或卵清蛋白（OVA）/完全弗氏佐剂（CFA）建立两种重度哮喘小鼠模型。通过腹腔注射DECMA-1（一种针对sE-钙黏蛋白的中和抗体）来评估sE-钙黏蛋白在重度哮喘中的作用。用重组sE-钙黏蛋白处理小鼠或THP-1来源的巨噬细胞，以探究sE-钙黏蛋白的促炎机制。重度哮喘患者的痰液sE-钙黏蛋白水平显著高于轻度至中度哮喘的健康受试者，且与痰液高迁移率族蛋白B1（HMGB1）水平和每日控制所需的糖皮质激素剂量呈正相关。变应原暴露显著增加了小鼠支气管肺泡灌洗液中的sE-钙黏蛋白水平。在两种重度哮喘模型中，DECMA-1治疗均显著减轻了变应原诱导的气道炎症和高反应性。当暴露于重组sE-钙黏蛋白时，THP-1来源的巨噬细胞中血管内皮生长因子（VEGF）表达显著上调，并且小鼠气道中的中性粒细胞和嗜酸性粒细胞浸润增加，同时VEGF和白细胞介素-6（IL-6）释放增加，而这两者均可通过ERK信号通路的药理学抑制作用得到抑制。综上所述，我们的数据表明sE-钙黏蛋白通过ERK依赖途径促成重度哮喘的气道炎症。
