Pretreatment with valproic acid alleviates pulmonary fibrosis through epithelial-mesenchymal transition inhibition in vitro and in vivo

被引：24

作者：

Chen, Lin ^{[1
,2
]}

Alam, Azeem ^{[2
]}

Pac-Soo, Aurelie ^{[2
]}

Chen, Qian ^{[2
]}

Shang, You ^{[3
]}

Zhao, Hailin ^{[2
]}

Yao, Shanglong ^{[1
]}

Ma, Daqing ^{[2
]}

机构：

[1] Huazhong Univ Sci & Technol, Tongji Med Coll, Union Hosp, Dept Anesthesiol,Inst Anesthesiol & Crit Care Med, Wuhan, Peoples R China

[2] Imperial Coll London, Chelsea & Westminster Hosp, Fac Med, Anesthet Pain Med & Intens Care,Dept Surg & Canc, London, England

[3] Huazhong Univ Sci & Technol, Inst Anesthesiol & Crit Care Med, Union Hosp, Dept Crit Care Med,Tongji Med Coll, Wuhan, Peoples R China

来源：

LABORATORY INVESTIGATION | 2021年 / 101卷 / 09期

基金：

中国国家自然科学基金;

关键词：

HISTONE DEACETYLASE INHIBITOR; ISCHEMIA-REPERFUSION; LUNG FIBROSIS; INJURY; PATHWAY; KINASE; EMT;

D O I：

10.1038/s41374-021-00617-2

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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-beta 1 (TGF-beta 1) 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-beta 1 and the expression of E-cadherin, vimentin, p-Smad2/3 and p-Akt was assessed. In addition, the effects of a TGF-beta 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-beta 1 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-beta 1 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.

引用

页码：1166 / 1175

页数：10

共 51 条

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