mAChRs activation induces epithelial-mesenchymal transition on lung epithelial cells.
mAChRs activation induces epithelial-mesenchymal transition on lung epithelial cells.
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mAChRs 激活诱导肺上皮细胞上皮-间质转化
DOI：
10.1186/1471-2466-14-53
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发表时间：
2014-03-31
影响因子：
3.1
通讯作者：
Cui YY
中科院分区：
文献类型：
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作者：
Yang K;Song Y;Tang YB;Xu ZP;Zhou W;Hou LN;Zhu L;Yu ZH;Chen HZ;Cui YY
上皮-间充质转化（EMT）已被认为是气道疾病和癌症发展的一个机制。在这里，我们探讨了乙酰胆碱（ACh）在EMT过程中的作用和参与的途径，以及mAChRs拮抗剂的作用。方法用乙酰胆碱类似物乙酰胆碱刺激人肺上皮细胞，采用western blot和免疫荧光法检测上皮和间充质标记蛋白。结果TGF-β1诱导肺泡上皮细胞（A549） E-cadherin表达降低，vimentin和α-SMA表达升高，非选择性mAChR拮抗剂阿托品明显消除其表达，乙酰胆碱酯酶抑制剂菲索斯汀则增强其表达。单独使用芥子碱也会发生EMT事件。TGF-β1可增强A549细胞的ChAT表达和ACh释放。有趣的是，ACh类似物carbachol也能在A549细胞和支气管上皮细胞（16HBE）中诱导EMT，并呈时间和浓度依赖性，选择性拮抗剂M1 （pirenzepine）和M3 (4-DAMP) machr可以消除对carbachol的诱导，而M2（甲氧曲明）拮抗剂则不能。此外，carbachol在EMT过程中诱导A549细胞产生TGF-β1。carbachl诱导的EMT是通过Smad2/3和ERK的磷酸化发生的，pirenzepine和4-DAMP可以抑制这种磷酸化。结论我们的研究结果首次表明，可能通过M1和M3的mAChR激活，诱导肺上皮细胞进行EMT，并为肺部重塑发生的气道疾病的新治疗策略提供了见解。
BackgroundEpithelial-mesenchymal transition (EMT) has been proposed as a mechanism in the progression of airway diseases and cancer. Here, we explored the role of acetylcholine (ACh) and the pathway involved in the process of EMT, as well as the effects of mAChRs antagonist.MethodsHuman lung epithelial cells were stimulated with carbachol, an analogue of ACh, and epithelial and mesenchymal marker proteins were evaluated using western blot and immunofluorescence analyses.ResultsDecreased E-cadherin expression and increased vimentin and α-SMA expression induced by TGF-β1 in alveolar epithelial cell (A549) were significantly abrogated by the non-selective mAChR antagonist atropine and enhanced by the acetylcholinesterase inhibitor physostigmine. An EMT event also occurred in response to physostigmine alone. Furthermore, ChAT express and ACh release by A549 cells were enhanced by TGF-β1. Interestingly, ACh analogue carbachol also induced EMT in A549 cells as well as in bronchial epithelial cells (16HBE) in a time- and concentration-dependent manner, the induction of carbachol was abrogated by selective antagonist of M1 (pirenzepine) and M3 (4-DAMP) mAChRs, but not by M2 (methoctramine) antagonist. Moreover, carbachol induced TGF-β1 production from A549 cells concomitantly with the EMT process. Carbachol-induced EMT occurred through phosphorylation of Smad2/3 and ERK, which was inhibited by pirenzepine and 4-DAMP.ConclusionsOur findings for the first time indicated that mAChR activation, perhaps via M1 and M3 mAChR, induced lung epithelial cells to undergo EMT and provided insights into novel therapeutic strategies for airway diseases in which lung remodeling occurs.
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影响因子：
3.3
作者：
Kage H;Borok Z
通讯作者：
Borok Z
影响因子：
4.8
作者：
Kong, Kok Choi;Billington, Charlotte K.;Penn, Raymond B.
通讯作者：
Penn, Raymond B.
影响因子：
6.1
作者：
Profita, Mirella;Bonanno, Anna;Gjomarkaj, Mark
通讯作者：
Gjomarkaj, Mark
影响因子：
24.3
作者：
Milara, Javier;Serrano, Adela;Cortijo, Julio
通讯作者：
Cortijo, Julio
DOI：
10.1038/nrrheum.2011.149
发表时间：
2011-10-25
期刊：
Nature reviews. Rheumatology
影响因子：
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作者：
通讯作者：
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