DEK-targeting aptamer DTA-64 attenuates bronchial EMT-mediated airway remodelling by suppressing TGF-β1/Smad, MAPK and PI3K signalling pathway in asthma.
DEK-targeting aptamer DTA-64 attenuates bronchial EMT-mediated airway remodelling by suppressing TGF-β1/Smad, MAPK and PI3K signalling pathway in asthma.
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DEK 靶向适体 DTA-64 通过抑制哮喘中 TGF-β 1/Smad、MAPK 和 PI3K 信号通路来减弱支气管 EMT 介导的气道重塑
DOI：
10.1111/jcmm.15942
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发表时间：
2020-12
影响因子：
5.3
通讯作者：
Yan G
中科院分区：
文献类型：
--
作者：
Song Y;Wang Z;Jiang J;Piao Y;Li L;Xu C;Piao H;Li L;Yan G
本研究旨在探讨靶向DEK的适体（DTA - 64）对小鼠和人支气管上皮细胞系BEAS - 2B中上皮 - 间质转化（EMT）介导的气道重塑的抑制作用及其机制。在卵清蛋白（OVA）诱导的哮喘小鼠中，DTA - 64显著减少了肺组织中嗜酸性粒细胞和中性粒细胞的浸润，降低了气道阻力以及杯状细胞的增殖。此外，DTA - 64减少了胶原沉积、支气管肺泡灌洗液（BALF）中转化生长因子β1（TGF - β1）水平以及血清中IgE水平，平衡了Th1/Th2/Th17比值，降低了间质蛋白（波形蛋白和α - 平滑肌肌动蛋白）水平，同时减弱了基质金属蛋白酶（MMP - 2和MMP - 9）以及核因子κB p65的活性。在体外实验中，我们使用TGF - β1诱导人上皮细胞系BEAS - 2B发生EMT。DEK过表达（ovDEK）或沉默（shDEK）分别上调或下调TGF - β1的表达，相反，TGF - β1暴露对DEK表达无影响。此外，ovDEK和TGF - β1协同促进EMT，而shDEK显著降低间质标志物并增加上皮标志物，从而抑制EMT。另外，shDEK抑制TGF - β1介导的信号通路中的关键蛋白，包括Smad2/3、Smad4、p38丝裂原活化蛋白激酶（MAPK）、细胞外调节蛋白激酶1/2（ERK1/2）、c - Jun氨基末端激酶（JNK）以及磷脂酰肌醇 - 3激酶/蛋白激酶B/哺乳动物雷帕霉素靶蛋白（PI3K/AKT/mTOR）。总之，DTA - 64对哮喘小鼠和BEAS - 2B的EMT的作用可能部分通过抑制TGF - β1/Smad、MAPK和PI3K信号通路来实现。DTA - 64可能是哮喘患者气道重塑管理的一种新的治疗选择。
This study is to investigate the inhibitory effects and mechanisms of DEK‐targeting aptamer (DTA‐64) on epithelial mesenchymaltransition (EMT)‐mediated airway remodelling in mice and human bronchial epithelial cell line BEAS‐2B. In the ovalbumin (OVA)‐induced asthmatic mice, DTA‐64 significantly reduced the infiltration of eosinophils and neutrophils in lung tissue, attenuated the airway resistance and the proliferation of goblet cells. In addition, DTA‐64 reduced collagen deposition, transforming growth factor 1 (TGF‐β1) level in BALF and IgE levels in serum, balanced Th1/Th2/Th17 ratio, and decreased mesenchymal proteins (vimentin and α‐SMA), as well as weekend matrix metalloproteinases (MMP‐2 and MMP‐9) and NF‐κB p65 activity. In the in vitro experiments, we used TGF‐β1 to induce EMT in the human epithelial cell line BEAS‐2B. DEK overexpression (ovDEK) or silencing (shDEK) up‐regulated or down‐regulated TGF‐β1 expression, respectively, on the contrary, TGF‐β1 exposure had no effect on DEK expression. Furthermore, ovDEK and TGF‐β1 synergistically promoted EMT, whereas shDEK significantly reduced mesenchymal markers and increased epithelial markers, thus inhibiting EMT. Additionally, shDEK inhibited key proteins in TGF‐β1‐mediated signalling pathways, including Smad2/3, Smad4, p38 MAPK, ERK1/2, JNK and PI3K/AKT/mTOR. In conclusion, the effects of DTA‐64 against EMT of asthmatic mice and BEAS‐2B might partially be achieved through suppressing TGF‐β1/Smad, MAPK and PI3K signalling pathways. DTA‐64 may be a new therapeutic option for the management of airway remodelling in asthma patients.
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DOI：
10.1038/labinvest.2016.109
发表时间：
2016-12
期刊：
Laboratory investigation; a journal of technical methods and pathology
影响因子：
--
作者：
通讯作者：
--
影响因子：
7.7
作者：
Chen, Hai-hua;Zhou, Xian-long;Yang, Jiong
通讯作者：
Yang, Jiong
影响因子：
16.6
作者：
Campa, Carlo C.;Silva, Rangel L.;Hirsch, Emilio
通讯作者：
Hirsch, Emilio
影响因子：
5.6
作者：
Lee, Kam-Fai;Tsai, Ming-Ming;Lin, Kwang-Huei
通讯作者：
Lin, Kwang-Huei
影响因子：
16.6
作者：
Mor-Vaknin N;Saha A;Legendre M;Carmona-Rivera C;Amin MA;Rabquer BJ;Gonzales-Hernandez MJ;Jorns J;Mohan S;Yalavarthi S;Pai DA;Angevine K;Almburg SJ;Knight JS;Adams BS;Koch AE;Fox DA;Engelke DR;Kaplan MJ;Markovitz DM
通讯作者：
Markovitz DM