DOCK2通过引发气道上皮-间质转化来促进哮喘的发展
2023/09/21
摘要
背景：上皮-间质转化（EMT）有助于气道重塑，这是哮喘的主要特征。DOCK2是参与血管重塑的先天免疫信号分子。
目的：但是，尚不清楚DOCK2在哮喘发展过程中是否在气道重塑中起作用。
方法：在这项研究中，我们发现DOCK2在用屋尘螨（HDM）提取物和人哮喘气道上皮处理的正常人支气管上皮细胞中均被高度诱导。在人支气管上皮细胞的EMT期间，DOCK2也被TGF-β1（转化生长因子β1）上调。重要的是，DOCK2的敲低抑制TGF-β1诱导的EMT，而DOCK2的过表达促进TGF-β1诱导的EMT。一致地，DOCK2缺乏抑制HDM诱导的哮喘肺中气道上皮的EMT，减轻上皮下纤维化并改善肺功能。
结果：这些数据表明DOCK2在EMT和哮喘发展中起重要作用。从机制上讲，DOCK2与转录因子FoxM1相互作用，后增强FoxM1与间充质标记基因启动子的结合，并进一步促进间充质标记基因的转录和表达，从而导致EMT。
结论：综上所述，我们的研究将DOCK2鉴定为HDM诱导的哮喘模型中气道EMT的新型调节剂，从而为哮喘的治疗提供了潜在的治疗靶标。
DOCK2 Promotes Asthma Development by Eliciting Airway Epithelial-Mesenchymal Transition.
Shi N, Zhang J, Chen SY,
Abstrast
Background: Epithelial-mesenchymal transition (EMT) contributes to airway remodeling, a predominant feature of asthma. DOCK2 (dedicator of cytokinesis 2) is an innate immune signaling molecule involved in vascular remodeling.However, it is unknown if DOCK2 plays a role in airway remodeling during asthma development.
Methods: In this study, we found that DOCK2 is highly induced in both normal human bronchial epithelial cells treated with house dust mite (HDM) extract and human asthmatic airway epithelium. DOCK2 is also upregulated by TGF-β1 (transforming growth factor β1) during EMT of human bronchial epithelial cells. Importantly, knockdown of DOCK2 inhibits, and overexpression of DOCK2 promotes, TGF-β1-induced EMT. Consistently, DOCK2 deficiency suppresses the EMT of airway epithelium, attenuates the subepithelial fibrosis, and improves pulmonary function in HDM-induced asthmatic lungs.
Results: These data suggest that DOCK2 plays an important role in EMT and asthma development. Mechanistically, DOCK2 interacts with transcription factor FoxM1 (forkhead box M1), which enhances FoxM1 binding to mesenchymal marker gene promoters and further promotes mesenchymal marker gene transcription and expression, leading to EMT.
Conclusions: Taken together, our study identifies DOCK2 as a novel regulator for airway EMT in an HDM-induced asthma model, thus providing a potential therapeutic target for treatment of asthma.
背景：上皮-间质转化（EMT）有助于气道重塑，这是哮喘的主要特征。DOCK2是参与血管重塑的先天免疫信号分子。
目的：但是，尚不清楚DOCK2在哮喘发展过程中是否在气道重塑中起作用。
方法：在这项研究中，我们发现DOCK2在用屋尘螨（HDM）提取物和人哮喘气道上皮处理的正常人支气管上皮细胞中均被高度诱导。在人支气管上皮细胞的EMT期间，DOCK2也被TGF-β1（转化生长因子β1）上调。重要的是，DOCK2的敲低抑制TGF-β1诱导的EMT，而DOCK2的过表达促进TGF-β1诱导的EMT。一致地，DOCK2缺乏抑制HDM诱导的哮喘肺中气道上皮的EMT，减轻上皮下纤维化并改善肺功能。
结果：这些数据表明DOCK2在EMT和哮喘发展中起重要作用。从机制上讲，DOCK2与转录因子FoxM1相互作用，后增强FoxM1与间充质标记基因启动子的结合，并进一步促进间充质标记基因的转录和表达，从而导致EMT。
结论：综上所述，我们的研究将DOCK2鉴定为HDM诱导的哮喘模型中气道EMT的新型调节剂，从而为哮喘的治疗提供了潜在的治疗靶标。
(中日友好医院呼吸与危重症医学科 万静萱 摘译 林江涛 审校)
(Am J Respir Cell Mol Biol 2023 Sep;69(3). doi: 10.1165/rcmb.2022-0273OC.IF: 5.373)
(Am J Respir Cell Mol Biol 2023 Sep;69(3). doi: 10.1165/rcmb.2022-0273OC.IF: 5.373)
DOCK2 Promotes Asthma Development by Eliciting Airway Epithelial-Mesenchymal Transition.
Shi N, Zhang J, Chen SY,
Abstrast
Background: Epithelial-mesenchymal transition (EMT) contributes to airway remodeling, a predominant feature of asthma. DOCK2 (dedicator of cytokinesis 2) is an innate immune signaling molecule involved in vascular remodeling.However, it is unknown if DOCK2 plays a role in airway remodeling during asthma development.
Methods: In this study, we found that DOCK2 is highly induced in both normal human bronchial epithelial cells treated with house dust mite (HDM) extract and human asthmatic airway epithelium. DOCK2 is also upregulated by TGF-β1 (transforming growth factor β1) during EMT of human bronchial epithelial cells. Importantly, knockdown of DOCK2 inhibits, and overexpression of DOCK2 promotes, TGF-β1-induced EMT. Consistently, DOCK2 deficiency suppresses the EMT of airway epithelium, attenuates the subepithelial fibrosis, and improves pulmonary function in HDM-induced asthmatic lungs.
Results: These data suggest that DOCK2 plays an important role in EMT and asthma development. Mechanistically, DOCK2 interacts with transcription factor FoxM1 (forkhead box M1), which enhances FoxM1 binding to mesenchymal marker gene promoters and further promotes mesenchymal marker gene transcription and expression, leading to EMT.
Conclusions: Taken together, our study identifies DOCK2 as a novel regulator for airway EMT in an HDM-induced asthma model, thus providing a potential therapeutic target for treatment of asthma.
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NO暴露对哮喘小鼠气道炎症和氧化应激的影响
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B细胞衍生的IL-10促进Bcl-3调节的哮喘过敏性增敏
