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Inhibition of EZH2 prevents acute respiratory distress syndrome (ARDS)-associated pulmonary fibrosis by regulating the macrophage polarization phenotype

BACKGROUND: We recently reported histone methyltransferase enhancer of zeste homolog 2 (EZH2) as a key epigenetic regulator that contributes to the dysfunction of innate immune responses to sepsis and subsequent lung injury by mediating the imbalance of macrophage polarization. However, the role of...

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Autores principales: Bao, Xiaowei, Liu, Xiandong, Liu, Na, Zhuang, Shougang, Yang, Qian, Ren, Huijuan, Zhao, Dongyang, Bai, Jianwen, Zhou, Xiaohui, Tang, Lunxian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255011/
https://www.ncbi.nlm.nih.gov/pubmed/34217280
http://dx.doi.org/10.1186/s12931-021-01785-x
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author Bao, Xiaowei
Liu, Xiandong
Liu, Na
Zhuang, Shougang
Yang, Qian
Ren, Huijuan
Zhao, Dongyang
Bai, Jianwen
Zhou, Xiaohui
Tang, Lunxian
author_facet Bao, Xiaowei
Liu, Xiandong
Liu, Na
Zhuang, Shougang
Yang, Qian
Ren, Huijuan
Zhao, Dongyang
Bai, Jianwen
Zhou, Xiaohui
Tang, Lunxian
author_sort Bao, Xiaowei
collection PubMed
description BACKGROUND: We recently reported histone methyltransferase enhancer of zeste homolog 2 (EZH2) as a key epigenetic regulator that contributes to the dysfunction of innate immune responses to sepsis and subsequent lung injury by mediating the imbalance of macrophage polarization. However, the role of EZH2 in acute respiratory distress syndrome (ARDS)-associated fibrosis remains poorly understood. METHODS: In this study, we investigated the role and mechanisms of EZH2 in pulmonary fibrosis in a murine model of LPS-induced ARDS and in ex-vivo cultured alveolar macrophages (MH-S) and mouse lung epithelial cell line (MLE-12) by using 3-deazaneplanocin A (3-DZNeP) and EZH2 the small interfering (si) RNA. RESULTS: We found that treatment with 3-DZNeP significantly ameliorated the LPS-induced direct lung injury and fibroproliferation by blocking EMT through TGF-β1/Smad signaling pathway and regulating shift of macrophage phenotypes. In the ex-vivo polarized alveolar macrophages cells, treatment with EZH2 siRNA or 3-DZNeP suppressed the M1 while promoted the M2 macrophage differentiation through modulating the STAT/SOCS signaling pathway and activating PPAR-γ. Moreover, we identified that blockade of EZH2 with 3-DZNeP suppressed the epithelial to mesenchymal transition (EMT) in co-cultured bronchoalveolar lavage fluid (BALF) and mouse lung epithelial cell line through down-regulation of TGF-β1, TGF-βR1, Smad2 while up-regulation of Smad7 expression. CONCLUSIONS: These results indicate that EZH2 is involved in the pathological process of ARDS-associated pulmonary fibrosis. Targeting EZH2 may be a potential therapeutic strategy to prevent and treat pulmonary fibrosis post ARDS.
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spelling pubmed-82550112021-07-06 Inhibition of EZH2 prevents acute respiratory distress syndrome (ARDS)-associated pulmonary fibrosis by regulating the macrophage polarization phenotype Bao, Xiaowei Liu, Xiandong Liu, Na Zhuang, Shougang Yang, Qian Ren, Huijuan Zhao, Dongyang Bai, Jianwen Zhou, Xiaohui Tang, Lunxian Respir Res Research BACKGROUND: We recently reported histone methyltransferase enhancer of zeste homolog 2 (EZH2) as a key epigenetic regulator that contributes to the dysfunction of innate immune responses to sepsis and subsequent lung injury by mediating the imbalance of macrophage polarization. However, the role of EZH2 in acute respiratory distress syndrome (ARDS)-associated fibrosis remains poorly understood. METHODS: In this study, we investigated the role and mechanisms of EZH2 in pulmonary fibrosis in a murine model of LPS-induced ARDS and in ex-vivo cultured alveolar macrophages (MH-S) and mouse lung epithelial cell line (MLE-12) by using 3-deazaneplanocin A (3-DZNeP) and EZH2 the small interfering (si) RNA. RESULTS: We found that treatment with 3-DZNeP significantly ameliorated the LPS-induced direct lung injury and fibroproliferation by blocking EMT through TGF-β1/Smad signaling pathway and regulating shift of macrophage phenotypes. In the ex-vivo polarized alveolar macrophages cells, treatment with EZH2 siRNA or 3-DZNeP suppressed the M1 while promoted the M2 macrophage differentiation through modulating the STAT/SOCS signaling pathway and activating PPAR-γ. Moreover, we identified that blockade of EZH2 with 3-DZNeP suppressed the epithelial to mesenchymal transition (EMT) in co-cultured bronchoalveolar lavage fluid (BALF) and mouse lung epithelial cell line through down-regulation of TGF-β1, TGF-βR1, Smad2 while up-regulation of Smad7 expression. CONCLUSIONS: These results indicate that EZH2 is involved in the pathological process of ARDS-associated pulmonary fibrosis. Targeting EZH2 may be a potential therapeutic strategy to prevent and treat pulmonary fibrosis post ARDS. BioMed Central 2021-07-03 2021 /pmc/articles/PMC8255011/ /pubmed/34217280 http://dx.doi.org/10.1186/s12931-021-01785-x Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Bao, Xiaowei
Liu, Xiandong
Liu, Na
Zhuang, Shougang
Yang, Qian
Ren, Huijuan
Zhao, Dongyang
Bai, Jianwen
Zhou, Xiaohui
Tang, Lunxian
Inhibition of EZH2 prevents acute respiratory distress syndrome (ARDS)-associated pulmonary fibrosis by regulating the macrophage polarization phenotype
title Inhibition of EZH2 prevents acute respiratory distress syndrome (ARDS)-associated pulmonary fibrosis by regulating the macrophage polarization phenotype
title_full Inhibition of EZH2 prevents acute respiratory distress syndrome (ARDS)-associated pulmonary fibrosis by regulating the macrophage polarization phenotype
title_fullStr Inhibition of EZH2 prevents acute respiratory distress syndrome (ARDS)-associated pulmonary fibrosis by regulating the macrophage polarization phenotype
title_full_unstemmed Inhibition of EZH2 prevents acute respiratory distress syndrome (ARDS)-associated pulmonary fibrosis by regulating the macrophage polarization phenotype
title_short Inhibition of EZH2 prevents acute respiratory distress syndrome (ARDS)-associated pulmonary fibrosis by regulating the macrophage polarization phenotype
title_sort inhibition of ezh2 prevents acute respiratory distress syndrome (ards)-associated pulmonary fibrosis by regulating the macrophage polarization phenotype
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255011/
https://www.ncbi.nlm.nih.gov/pubmed/34217280
http://dx.doi.org/10.1186/s12931-021-01785-x
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