Department of Pediatrics, The Affiliated Hospital of Qingdao University, Qingdao, China.
Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
Int Arch Allergy Immunol. 2021;182(6):479-488. doi: 10.1159/000512873. Epub 2021 Feb 25.
The homeodomain transcription factor sine oculis homeobox homolog 1 (Six1) plays a crucial role in embryogenesis and is not expressed in normal adult tissue but is expressed in many pathological processes, including airway remodelling in asthma. The current study aimed to reveal the effects of Six1 in regulating the airway remodelling and its possible mechanism.
A mouse model of ovalbumin-induced asthma-associated airway wall remodelling and a bronchial epithelial cell (16HBE) model of transforming growth factor β1 (TGFβ1)-induced epithelial-mesenchymal transition (EMT) were used to investigate the role of Six1. Then, 16HBE cells were transformed with Six1 expression vectors and treated with a TGFβ1 pathway inhibitor to determine the role of Six1 in EMT. The effect of Six1 and its possible mechanism were assessed by immunohistochemistry, RT-PCR, and Western blot.
Six1 expression was elevated in the lungs in an OVA mouse model of allergic asthma and in 16HBE cells treated with TGFβ1. Six1 overexpression promoted an EMT-like phenotype with a decreased protein expression of E-cadherin and increased protein expression of α-smooth muscle actin (α-SMA) as well as fibronectin in 16HBE cells; these effects appeared to promote TGFβ1 and phospho-Smad2 (pSmad2) production, which are the main products of the TGFβ1/Smad signalling pathway, which could be reduced by a TGFβ1 inhibitor.
These data reveal that Six1 and TGFβ1 are potentially a part of an autocrine feedback loop that induces EMT, and these factors can be reduced by blocking the TGFβ1/Smad signalling pathway. As such, these factors may represent a promising novel therapeutic target for airway remodelling in asthma.
同源盒转录因子 sine oculis 同源盒基因 1（Six1）在家胚胎发生中起着至关重要的作用，在正常成人组织中不表达，但在许多病理过程中表达，包括哮喘中的气道重塑。本研究旨在揭示 Six1 在调节气道重塑中的作用及其可能的机制。
使用卵清蛋白诱导的哮喘相关气道壁重塑小鼠模型和转化生长因子 β1（TGFβ1）诱导的上皮-间充质转化（EMT）的支气管上皮细胞（16HBE）模型来研究 Six1 的作用。然后，用 Six1 表达载体转化 16HBE 细胞，并用 TGFβ1 通路抑制剂处理，以确定 Six1 在 EMT 中的作用。通过免疫组织化学、RT-PCR 和 Western blot 评估 Six1 的作用及其可能的机制。
在卵清蛋白诱导的过敏性哮喘小鼠模型和用 TGFβ1 处理的 16HBE 细胞中，Six1 的表达升高。Six1 过表达促进 EMT 样表型，导致 16HBE 细胞中 E-钙黏蛋白蛋白表达降低，α-平滑肌肌动蛋白（α-SMA）和纤维连接蛋白蛋白表达增加；这些作用似乎促进了 TGFβ1 和磷酸化 Smad2（pSmad2）的产生，这是 TGFβ1/Smad 信号通路的主要产物，可被 TGFβ1 抑制剂减少。
这些数据表明，Six1 和 TGFβ1 可能是诱导 EMT 的自分泌反馈环的一部分，并且这些因子可通过阻断 TGFβ1/Smad 信号通路来减少。因此，这些因子可能代表哮喘气道重塑的有前途的新型治疗靶标。
