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MiRNA-451a inhibits airway remodeling by targeting Cadherin 11 in an allergic asthma model of neonatal mice.

MiRNA-451a 通过靶向钙黏蛋白 11 抑制新生小鼠过敏性哮喘模型气道重塑。

  • 影响因子:3.32
  • DOI:10.1016/j.intimp.2020.106440
  • 作者列表:"Wang T","Zhou Q","Shang Y
  • 发表时间:2020-03-29
Abstract

:Airway remodeling happens in childhood asthma, in parallel with, but not necessarily subsequent to, airway inflammation. The differentiation of airway epithelial cells into myofibroblasts via epithelial-mesenchymal-transition (EMT) is one of the mechanisms underlying airway remodeling. This study aimed at identifying novel molecules involved in pediatric asthma-associated airway remodeling. Asthma model was established by challenging C57BL/6 mouse pups with ovalbumin (OVA). We found that the expression of Cadherin 11 (CDH11), a type II cadherin, was increased by OVA treatments in the airway epithelium. Our earlier microarray data suggested miRNA-451a-5p (miRNA-451a) as a potential regulator of CDH11. In contrast to CDH11, miRNA-451a expression decreased in the asthmatic lung. MiRNA-451a was then packaged into a lentivirus vector and systematically given to the asthmatic pups. Our data indicated that OVA-induced infiltration of inflammatory cells, including eosnophils, neutrophils, macrophages and lymphocytes, was reduced by miRNA-451a over-expression. EMT was initiated in asthmatic mice as demonstrated by increased alpha-smooth muscle actin (α-SMA) positive cells present in airway epithelium, which was inhibited by miRNA-451a. CDH11 elevation in vivo was also inhibited by miRNA-451a. Dual-Luciferase analysis further showed CDH11 as a novel valid target of miRNA-451a. Additionally, in vitro, EMT was triggered in human 16HBE airway epithelial cells by pro-fibrotic transforming growth factor β (TGF-β). Corresponding to the anti-EMT effects observed in vivo, miRNA-451a also inhibited TGF-β-induced collagen deposition in cultured airway epithelial cells by targeting in CDH11. In summary, our study demonstrates that the deregulated miRNA-451a-CDH11 axis contributes to airway remodeling in childhood asthma.

摘要

: 气道重塑发生在儿童哮喘中,与气道炎症并行,但不一定继发于气道炎症。气道上皮细胞通过上皮间质转化 (EMT) 向肌成纤维细胞分化是气道重塑的机制之一。本研究旨在鉴定参与儿童哮喘相关气道重塑的新型分子。采用卵清蛋白 (OVA) 挑战 C57BL/6 小鼠幼鼠建立哮喘模型。我们发现气道上皮中 OVA 处理增加了钙黏蛋白 11 (CDH11) 的表达,这是一种 II 型钙黏蛋白。我们早期的微阵列数据表明 miRNA-451a-5p (miRNA-451a) 是 cdh11 的潜在调控因子。与 CDH11 相反,miRNA-451a 在哮喘肺组织中表达降低。然后将 MiRNA-451a 包装成慢病毒载体,系统地给予哮喘幼鼠。我们的数据表明,OVA 诱导的炎性细胞浸润,包括嗜酸性粒细胞、中性粒细胞、巨噬细胞和淋巴细胞,通过 miRNA-451a 过表达减少。EMT 在哮喘小鼠中启动,表现为气道上皮中 α-平滑肌肌动蛋白 (α-SMA) 阳性细胞增加,其被 miRNA-451a 抑制。CDH11 在体内的升高也被 miRNA-451a 抑制。双荧光素酶分析进一步表明 CDH11 是 miRNA-451a 的一个新的有效靶点。此外,在体外,促纤维化转化生长因子 β (TGF-β) 在人 16HBE 气道上皮细胞中触发 EMT。与体内观察到的抗 EMT 作用相对应,miRNA-451a 还通过靶向 cdh11 抑制 TGF-β 诱导的气道上皮细胞胶原沉积。总之,我们的研究表明,失调的 miRNA-451a-CDH11 轴有助于儿童哮喘的气道重塑。

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