Pretreatment with valproic acid alleviates pulmonary fibrosis through epithelial-mesenchymal transition inhibition in vitro and in vivo.
Pretreatment with valproic acid alleviates pulmonary fibrosis through epithelial-mesenchymal transition inhibition in vitro and in vivo.
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丙戊酸预处理通过体外和体内上皮-间质转化抑制减轻肺纤维化
DOI：
10.1038/s41374-021-00617-2
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发表时间：
2021-09
期刊：
影响因子：
--
通讯作者：
Ma D
中科院分区：
文献类型：
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作者：
Chen L;Alam A;Pac-Soo A;Chen Q;Shang Y;Zhao H;Yao S;Ma D
上皮-间质转化（EMT）在肺纤维化的发展中起着至关重要的作用。本研究旨在探讨丙戊酸（VPA）在体外和体内对 EMT 的影响。在体外，通过在人肺泡上皮细胞系（A549）中施用转化生长因子-β1（TGF-β1）来诱导 EMT。随后在不同时间点评估 VPA (0.1–3mM) 对 EMT 的剂量效应。在施用TGF-β1之前应用VPA(1 mM)并评估E-钙粘蛋白、波形蛋白、p-Smad2/3和p-Akt的表达。此外，还评估了TGF-β I型受体抑制剂（A8301）和PI3K-Akt抑制剂（LY294002）对EMT的影响。在体内，通过评估存活率、体重和组织病理学变化等变量来评估VPA对博来霉素诱导的肺纤维化的影响，同时还评估了肺组织中E-钙粘蛋白和波形蛋白的表达。 A8301 和 LY294002 用于确定该模型中涉及的细胞信号传导途径。在 A549 细胞中先于 TGF-β1 施用 VPA 以时间和浓度依赖性方式阻止 EMT。 VPA 预处理下调 p-Smad2/3 和 p-Akt 的表达。 A8301 给药增加了 E-钙粘蛋白的表达并减少了波形蛋白的表达。 LY294002 抑制 TGF-β1 诱导的 Akt 磷酸化，但未能阻止 EMT。 VPA 预处理既提高了肺纤维化小鼠的存活率，又防止了体重减轻。有趣的是，VPA 和 A8301 都能预防 EMT 并促进肺结构的改善。总体而言，VPA 预处理通过抑制小鼠的 EMT 来减轻肺纤维化的发展，这与 Smad2/3 失活有关，但不涉及 Akt 细胞信号。本研究调查了丙戊酸 (VPA) 对上皮间质转化 (EMT) 的影响。在体外，VPA 以时间和浓度依赖性方式预防 EMT。在体内，VPA 预处理可通过抑制小鼠的 EMT 来减轻肺纤维化的发展，这与 Smad2/3 失活有关，但不涉及 Akt 信号。
Epithelial–mesenchymal transition (EMT) plays a crucial role in the development of pulmonary fibrosis. This study aims to investigate the effects of valproic acid (VPA) on EMT in vitro and in vivo. In vitro, EMT was induced by the administration of transforming growth factor-β1 (TGF-β1) in a human alveolar epithelial cell line (A549). The dose effects of VPA (0.1–3 mM) on EMT were subsequently evaluated at different timepoints. VPA (1 mM) was applied prior to the administration of TGF-β1 and the expression of E-cadherin, vimentin, p-Smad2/3 and p-Akt was assessed. In addition, the effects of a TGF-β type I receptor inhibitor (A8301) and PI3K-Akt inhibitor (LY294002) on EMT were evaluated. In vivo, the effects of VPA on bleomycin-induced lung fibrosis were evaluated by assessing variables such as survival rate, body weight and histopathological changes, whilst the expression of E-cadherin and vimentin in lung tissue was also evaluated. A8301 and LY294002 were used to ascertain the cellular signaling pathways involved in this model. The administration of VPA prior to TGF-β1 in A549 cells prevented EMT in both a time- and concentration-dependent manner. Pretreatment with VPA downregulated the expression of both p-Smad2/3 and p-Akt. A8301 administration increased the expression of E-cadherin and reduced the expression of vimentin. LY294002 inhibited Akt phosphorylation induced by TGF-β1 but failed to prevent EMT. Pretreatment with VPA both increased the survival rate and prevented the loss of body weight in mice with pulmonary fibrosis. Interestingly, both VPA and A8301 prevented EMT and facilitated an improvement in lung structure. Overall, pretreatment with VPA attenuated the development of pulmonary fibrosis by inhibiting EMT in mice, which was associated with Smad2/3 deactivation but without Akt cellular signal involvement. This study investigated the effect of valproic acid (VPA) on epithelial–mesenchymal transition (EMT). In vitro, VPA prevents EMT in a time- and concentration-dependent manner. In vivo, pretreatment with VPA attenuates pulmonary fibrosis development through EMT inhibition in mice, which was associated with Smad2/3 deactivation but without Akt signal involvement.