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Identification of anoctamin 1 (ANO1) as a key driver of esophageal epithelial proliferation in eosinophilic esophagitis.

嗜酸细胞蛋白酶 1 (anoctamin 1,ANO1) 作为嗜酸细胞性食管炎食管上皮增生的关键驱动因子的鉴定。

  • 影响因子:6.87
  • DOI:10.1016/j.jaci.2019.07.049
  • 作者列表:"Vanoni S","Zeng C","Marella S","Uddin J","Wu D","Arora K","Ptaschinski C","Que J","Noah T","Waggoner L","Barski A","Kartashov A","Rochman M","Wen T","Martin L","Spence J","Collins M","Mukkada V","Putnam P","Naren A","Chehade M","Rothenberg ME","Hogan SP
  • 发表时间:2020-01-01
Abstract

BACKGROUND:The pathology of eosinophilic esophagitis (EoE) is characterized by eosinophil-rich inflammation, basal zone hyperplasia (BZH), and dilated intercellular spaces, and the underlying processes that drive the pathologic manifestations of the disease remain largely unexplored. OBJECTIVE:We sought to investigate the involvement of the calcium-activated chloride channel anoctamin 1 (ANO1) in esophageal proliferation and the histopathologic features of EoE. METHODS:We examined mRNA and protein expression of ANO1 in esophageal biopsy samples from patients with EoE and in mice with EoE. We performed molecular and cellular analyses and ion transport assays on an in vitro esophageal epithelial 3-dimensional model system (EPC2-ALI) and murine models of EoE to define the relationship between expression and function of ANO1 and esophageal epithelial proliferation in patients with EoE. RESULTS:We observed increased ANO1 expression in esophageal biopsy samples from patients with EoE and in mice with EoE. ANO1 was expressed within the esophageal basal zone, and expression correlated positively with disease severity (eosinophils/high-power field) and BZH. Using an in vitro esophageal epithelial 3-dimensional model system revealed that ANO1 undergoes chromatin modification and rapid upregulation of expression after IL-13 stimulation, that ANO1 is the primary apical IL-13-induced Cl- transport mechanism within the esophageal epithelium, and that loss of ANO1-dependent Cl- transport abrogated esophageal epithelial proliferation. Mechanistically, ANO1-dependent regulation of basal cell proliferation was associated with modulation of TP63 expression and phosphorylated cyclin-dependent kinase 2 levels. CONCLUSIONS:These data identify a functional role for ANO1 in esophageal cell proliferation and BZH in patients with EoE and provide a rationale for pharmacologic intervention of ANO1 function in patients with EoE.

摘要

背景: 嗜酸性粒细胞性食管炎 (EoE) 的病理特征是嗜酸性粒细胞丰富的炎症,基底带增生 (BZH),细胞间隙扩张, 驱动疾病病理表现的潜在过程在很大程度上仍未被探索。 目的: 探讨钙激活的氯离子通道蛋白 1 (anoctamin 1,ANO1) 在食管上皮细胞增生中的作用及其病理意义。 方法: 检测 EoE 患者和 EoE 小鼠食管活检标本中 ANO1 的 mRNA 和蛋白表达。我们对体外食管上皮三维模型系统 (EPC2-ALI) 进行了分子和细胞分析以及离子转运检测。和小鼠 EoE 模型,以确定 ANO1 的表达和功能与 EoE 患者食管上皮增殖的关系。 结果: 我们在 EoE 患者和 EoE 小鼠的食管活检样本中观察到 ANO1 表达增加。ANO1 在食管基底带内表达,表达与疾病严重程度 (嗜酸性粒细胞/高倍视野) 和 BZH 呈正相关。使用体外食管上皮三维模型系统发现,ANO1 在 IL-13 刺激后经历染色质修饰和表达的快速上调, ANO1 是食管上皮内主要的顶端 IL-13-induced Cl-转运机制,ANO1-dependent Cl-转运的丧失消除了食管上皮增生。从机制上讲,ANO1-dependent 调节基底细胞增殖与调节 TP63 表达和磷酸化细胞周期蛋白依赖性激酶 2 水平有关。 结论: 这些数据确定了 ANO1 在 EoE 患者食管细胞增殖和 BZH 中的功能作用,并为药物干预 EoE 患者 ANO1 功能提供了理论基础。

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作者列表:["Shang L","Pei QS","Xu D","Liu JY","Liu J"]

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