间充质干细胞通过Wnt /β-catenin信号通路减少哮喘大鼠肺中的气道重塑
2021/01/28
摘要
目的：哮喘是一种慢性肺炎性疾病，其特征在于过量的白细胞渗入呼吸道。我们使用大鼠模型探讨了间充质干细胞（MSCs）在治疗过敏性哮喘中的潜在机制。
材料和方法：用卵清蛋白（OVA）和氢氧化铝乳液致敏，然后腹膜内注射，然后用雾化的OVA激发致敏的大鼠。在变应原激发之前，向模型大鼠注射MSC和MSC来源的外泌体。同时，在6组大鼠中有2组注射了Wnt激动剂BML-284。气道炎症程度通过支气管肺泡灌洗液（BALF）以及苏木精和伊红（HE）染色确定。气道重塑程度通过Masson染色评估；进行了Western blotting（WB）和实时聚合酶链反应（PCR），以评估Wnt /β-catenin信号通路相关因子以及肺组织中上皮-间质转化（EMT）相关蛋白的表达。
结果：我们显示，在被OVA致敏和激发的大鼠中，注射MSC和MSC来源的外泌体可显着减少BALF中的细胞总数和免疫细胞数，杯状细胞增殖和胶原沉积。而且，注射BML-284后，BALF细胞的数目和胶原沉积显着增加。 WB和实时PCR显示，MSC和MSC来源的外泌体通过限制Wnt /β-catenin信号通路显著抑制气道重塑和EMT，而额外注射BML-284则抑制MSC及其外泌体的作用，增加EMT气道上皮的形成和气道重塑的加重。
结论：MSC可抑制哮喘大鼠肺中的气道慢性过敏性炎症，并减少气道重塑和气道上皮的EMT。此过程部分归因于MSC产生的外泌体对Wnt /β-catenin信号通路的抑制。
MSCs reduce airway remodeling in the lungs of asthmatic rats through the Wnt/β-catenin signaling pathway
Song J, Zhu XM, Wei QY.
Abstract：
OBJECTIVE: Asthma is a chronic pulmonary inflammatory disease characterized by excessive infiltration of leukocytes into the respiratory tract. We explored the underlying mechanisms of mesenchymal stem cells (MSCs) in the treatment of allergic asthma using a rat model.
MATERIALS AND METHODS:The rats were sensitized with ovalbumin (OVA) and an aluminium hydroxide emulsion, which were injected intraperitoneally, and then the sensitized rats were challenged with aerosolized OVA. Before the allergen challenge, the model rats were injected with MSCs and MSC-derived exosomes. At the same time, 2 out of the 6 groups of rats were injected with BML-284, a Wnt agonist. The degree of airway inflammation was determined by bronchoalveolar lavage fluid (BALF) and haematoxylin and eosin (H&E) staining; the degree of airway remodelling was assessed by Masson staining; Western blotting (WB) and real-time polymerase chain reaction (PCR) were performed to evaluate Wnt/β-catenin signalling pathway-related factors and the expression of epithelial-mesenchymal transition (EMT)-related proteins in lung tissues.
RESULTS:We showed that among the rats that were sensitized and challenged with OVA, the injection of MSCs and MSC-derived exosomes significantly reduced the total number of cells and the number of immune cells in BALF, proliferation of goblet cells and collagen deposition. Moreover, the number of BALF cells and collagen deposition increased significantly after the injection of BML-284. WB and real-time PCR showed that MSCs and MSC-derived exosomes significantly inhibited airway remodelling and EMT by restricting the Wnt/β-catenin signalling pathway, while additional injection of BML-284 suppressed the effects of MSCs and their exosomes, increased the EMT of the airway epithelium and exacerbated airway remodelling.
CONCLUSIONS:MSCs inhibit chronic allergic inflammation of the airway and reduce airway remodelling and EMT of the airway epithelium in the lungs of asthmatic rats. This process is partly attributed to the inhibition of the Wnt/β-catenin signalling pathway by MSC-derived exosomes.
目的：哮喘是一种慢性肺炎性疾病，其特征在于过量的白细胞渗入呼吸道。我们使用大鼠模型探讨了间充质干细胞（MSCs）在治疗过敏性哮喘中的潜在机制。
材料和方法：用卵清蛋白（OVA）和氢氧化铝乳液致敏，然后腹膜内注射，然后用雾化的OVA激发致敏的大鼠。在变应原激发之前，向模型大鼠注射MSC和MSC来源的外泌体。同时，在6组大鼠中有2组注射了Wnt激动剂BML-284。气道炎症程度通过支气管肺泡灌洗液（BALF）以及苏木精和伊红（HE）染色确定。气道重塑程度通过Masson染色评估；进行了Western blotting（WB）和实时聚合酶链反应（PCR），以评估Wnt /β-catenin信号通路相关因子以及肺组织中上皮-间质转化（EMT）相关蛋白的表达。
结果：我们显示，在被OVA致敏和激发的大鼠中，注射MSC和MSC来源的外泌体可显着减少BALF中的细胞总数和免疫细胞数，杯状细胞增殖和胶原沉积。而且，注射BML-284后，BALF细胞的数目和胶原沉积显着增加。 WB和实时PCR显示，MSC和MSC来源的外泌体通过限制Wnt /β-catenin信号通路显著抑制气道重塑和EMT，而额外注射BML-284则抑制MSC及其外泌体的作用，增加EMT气道上皮的形成和气道重塑的加重。
结论：MSC可抑制哮喘大鼠肺中的气道慢性过敏性炎症，并减少气道重塑和气道上皮的EMT。此过程部分归因于MSC产生的外泌体对Wnt /β-catenin信号通路的抑制。
（中日友好医院呼吸与危重症医学科 李春晓 摘译 林江涛 审校）
（Eur Rev Med Pharmacol Sci, 2020, 24(21): 11199-11211.）
（Eur Rev Med Pharmacol Sci, 2020, 24(21): 11199-11211.）
MSCs reduce airway remodeling in the lungs of asthmatic rats through the Wnt/β-catenin signaling pathway
Song J, Zhu XM, Wei QY.
Abstract：
OBJECTIVE: Asthma is a chronic pulmonary inflammatory disease characterized by excessive infiltration of leukocytes into the respiratory tract. We explored the underlying mechanisms of mesenchymal stem cells (MSCs) in the treatment of allergic asthma using a rat model.
MATERIALS AND METHODS:The rats were sensitized with ovalbumin (OVA) and an aluminium hydroxide emulsion, which were injected intraperitoneally, and then the sensitized rats were challenged with aerosolized OVA. Before the allergen challenge, the model rats were injected with MSCs and MSC-derived exosomes. At the same time, 2 out of the 6 groups of rats were injected with BML-284, a Wnt agonist. The degree of airway inflammation was determined by bronchoalveolar lavage fluid (BALF) and haematoxylin and eosin (H&E) staining; the degree of airway remodelling was assessed by Masson staining; Western blotting (WB) and real-time polymerase chain reaction (PCR) were performed to evaluate Wnt/β-catenin signalling pathway-related factors and the expression of epithelial-mesenchymal transition (EMT)-related proteins in lung tissues.
RESULTS:We showed that among the rats that were sensitized and challenged with OVA, the injection of MSCs and MSC-derived exosomes significantly reduced the total number of cells and the number of immune cells in BALF, proliferation of goblet cells and collagen deposition. Moreover, the number of BALF cells and collagen deposition increased significantly after the injection of BML-284. WB and real-time PCR showed that MSCs and MSC-derived exosomes significantly inhibited airway remodelling and EMT by restricting the Wnt/β-catenin signalling pathway, while additional injection of BML-284 suppressed the effects of MSCs and their exosomes, increased the EMT of the airway epithelium and exacerbated airway remodelling.
CONCLUSIONS:MSCs inhibit chronic allergic inflammation of the airway and reduce airway remodelling and EMT of the airway epithelium in the lungs of asthmatic rats. This process is partly attributed to the inhibition of the Wnt/β-catenin signalling pathway by MSC-derived exosomes.
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对2型炎症型未控制持续性哮喘治疗中的关键问题的认识
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人骨髓间充质干细胞治疗急性哮喘小鼠模型气道炎症的频率评价
