Andrographolide attenuates epithelial-mesenchymal transition induced by TGF-β1 in alveolar epithelial cells.
Andrographolide attenuates epithelial-mesenchymal transition induced by TGF-β1 in alveolar epithelial cells.
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穿心莲内酯减弱肺泡上皮细胞中 TGF-β1 诱导的上皮间质转化
DOI：
10.1111/jcmm.15665
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发表时间：
2020-09
影响因子：
5.3
通讯作者：
He J
中科院分区：
文献类型：
--
作者：
Li J;Liu J;Yue W;Xu K;Cai W;Cui F;Li Z;Wang W;He J
穿心莲内酯(Andro)是中草药穿心莲中的一种成分，可减轻啮齿动物的肺纤维化。然而，Andro是否以及如何减轻转化生长因子-β-1诱导的上皮-间充质转化仍不清楚。本研究旨在探讨Andro对转化生长因子-β-1诱导的人肺泡上皮细胞内皮细胞转化的影响及其机制。我们发现Andro抑制转化生长因子-β-1诱导的肺泡上皮A549细胞上皮细胞转化及相关转录因子的表达。Andro还减少了转化生长因子-β1诱导的细胞迁移和促纤维化因子(即CCN-2、转化生长因子-β1)、基质金属蛋白酶(即MMP2、MMP9)和细胞外基质成分(即胶原1)的合成，提示Andro对转化生长因子-β1诱导的EMT样细胞行为有抑制作用。从机制上讲，Andro不仅抑制转化生长因子-β1诱导的Smad2/3磷酸化和Smad4核转位，而且抑制转化生长因子-ERK1/2诱导的A549细胞ERK1/2磷酸化和核转位。Alk5抑制剂(SB431542)或ERK1/2抑制剂(SCH772984和PD98059)可显著降低转化生长因子-β-1诱导的细胞内ROS生成和β-4的表达，增加抗氧化剂超氧化物歧化酶2(SOD2)的表达，表明Andro对转化生长因子-β-1诱导的氧化应激具有抑制作用，而氧化应激与转化生长因子-NOX1的作用密切相关。此外，Andro显著减弱转化生长因子-β1诱导的Sirt1和Forkhead box O3(FOXO_3)的下调，提示Andro部分通过激活Sirt1/FOXO_3介导的抗氧化应激途径来保护血管内皮细胞免受EMT的影响。结论：Andro通过抑制Smad2/3和β1/2信号通路抑制转化生长因子-ERK1诱导的血管内皮细胞内皮细胞转分化，并与SIRT1/FOXO 3介导的抗氧化应激通路的激活密切相关。
Andrographolide (Andro), a component from Chinese medicinal herb Andrographis paniculata, could alleviate pulmonary fibrosis in rodents. Yet, whether and how Andro mitigates epithelial‐mesenchymal transition (EMT) induced by TGF‐β1 remain unknown. This study aimed to explore the effect of Andro on TGF‐β1‐induced EMT in human alveolar epithelial cells (AECs) and the mechanisms involved. We illustrated that Andro inhibited TGF‐β1‐induced EMT and EMT‐related transcription factors in alveolar epithelial A549 cells. Andro also reduced TGF‐β1‐induced cell migration and synthesis of pro‐fibrotic factors (ie CCN‐2, TGF‐β1), matrix metalloproteinases (ie MMP‐2, MMP‐9) and extracellular matrix (ECM) components (ie collagen 1), implying the inhibiting effect of Andro on TGF‐β1‐induced EMT‐like cell behaviours. Mechanistically, Andro treatment not only repressed TGF‐β1‐induced Smad2/3 phosphorylation and Smad4 nuclear translocation, but also suppressed TGF‐β1‐induced Erk1/2 phosphorylation and nuclear translocation in A549 cells. And treatment with ALK5 inhibitor (SB431542) or Erk1/2 inhibitors (SCH772984 and PD98059) remarkably reduced EMT evoked by TGF‐β1. In addition, Andro also reduced TGF‐β1‐induced intracellular ROS generation and NOX4 expression, and elevated antioxidant superoxide dismutase 2 (SOD2) expression, demonstrating the inhibiting effect of Andro on TGF‐β1‐induced oxidative stress, which is closely linked to EMT. Furthermore, Andro remarkably attenuated TGF‐β1‐induced down‐regulation of sirtuin1 (Sirt1) and forkhead box O3 (FOXO3), implying that Andro protects AECs from EMT partially by activating Sirt1/FOXO3‐mediated anti‐oxidative stress pathway. In conclusion, Andro represses TGF‐β1‐induced EMT in AECs by suppressing Smad2/3 and Erk1/2 signalling pathways and is also closely linked to the activation of sirt1/FOXO3‐mediated anti‐oxidative stress pathway.
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影响因子：
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