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Extracellular HSP90α Interacts With ER Stress to Promote Fibroblasts Activation Through PI3K/AKT Pathway in Pulmonary Fibrosis

Pulmonary fibrosis is characterized by alveolar epithelial cell injury, lung fibroblast proliferation, differentiation, and extracellular matrix (ECM) deposition. Our previous study indicated that extracellular HSP90α (eHSP90α) promotes pulmonary fibrosis by activating the MAPK signaling pathway. Th...

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Autores principales: Zhang, Jinming, Zhong, Wenshan, Liu, Yuanyuan, Chen, Weimou, Lu, Ye, Zeng, Zhaojin, Qiao, Yujie, Huang, Haohua, Wan, Xuan, Li, Wei, Meng, Xiaojing, Zou, Fei, Cai, Shaoxi, Dong, Hangming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420756/
https://www.ncbi.nlm.nih.gov/pubmed/34497513
http://dx.doi.org/10.3389/fphar.2021.708462
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author Zhang, Jinming
Zhong, Wenshan
Liu, Yuanyuan
Chen, Weimou
Lu, Ye
Zeng, Zhaojin
Qiao, Yujie
Huang, Haohua
Wan, Xuan
Li, Wei
Meng, Xiaojing
Zou, Fei
Cai, Shaoxi
Dong, Hangming
author_facet Zhang, Jinming
Zhong, Wenshan
Liu, Yuanyuan
Chen, Weimou
Lu, Ye
Zeng, Zhaojin
Qiao, Yujie
Huang, Haohua
Wan, Xuan
Li, Wei
Meng, Xiaojing
Zou, Fei
Cai, Shaoxi
Dong, Hangming
author_sort Zhang, Jinming
collection PubMed
description Pulmonary fibrosis is characterized by alveolar epithelial cell injury, lung fibroblast proliferation, differentiation, and extracellular matrix (ECM) deposition. Our previous study indicated that extracellular HSP90α (eHSP90α) promotes pulmonary fibrosis by activating the MAPK signaling pathway. Thus, treatment with 1G6-D7 (a selective HSP90α monoclonal antibody) to antagonize eHSP90α could effectively ameliorate fibrosis. This study aimed to elucidate the mechanism underlying the effects of eHSP90α in pulmonary fibrosis by focusing on its link with endoplasmic reticulum (ER) stress. Our results showed that eHSP90α promoted lung fibroblast differentiation by activating ER stress. Treatment with the ER stress inhibitor tauroursodeoxycholate (TUDCA) or glucose-regulated protein 78 kDa (GRP78) depletion significantly abrogated the effect of eHSP90α on ER stress and fibroblast activation. In addition, eHSP90α induced ER stress in fibroblasts via the phosphoinositide-4,5-bisphosphate 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway, which could be blocked by the PI3K/AKT inhibitor LY294002, and blockade of eHSP90α by 1G6-D7 markedly inhibited ER stress in the model, indicating preventive and therapeutic applications. Intriguingly, we observed that TUDCA effectively reduced the secretion of eHSP90α in vitro and in vivo. In conclusion, this study shows that the interaction between eHSP90α and ER stress plays a crucial role in pulmonary fibrosis, indicating a positive feedback in lung fibroblasts. Targeting eHSP90α and alleviating fibroblast ER stress may be promising therapeutic approaches for pulmonary fibrosis.
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spelling pubmed-84207562021-09-07 Extracellular HSP90α Interacts With ER Stress to Promote Fibroblasts Activation Through PI3K/AKT Pathway in Pulmonary Fibrosis Zhang, Jinming Zhong, Wenshan Liu, Yuanyuan Chen, Weimou Lu, Ye Zeng, Zhaojin Qiao, Yujie Huang, Haohua Wan, Xuan Li, Wei Meng, Xiaojing Zou, Fei Cai, Shaoxi Dong, Hangming Front Pharmacol Pharmacology Pulmonary fibrosis is characterized by alveolar epithelial cell injury, lung fibroblast proliferation, differentiation, and extracellular matrix (ECM) deposition. Our previous study indicated that extracellular HSP90α (eHSP90α) promotes pulmonary fibrosis by activating the MAPK signaling pathway. Thus, treatment with 1G6-D7 (a selective HSP90α monoclonal antibody) to antagonize eHSP90α could effectively ameliorate fibrosis. This study aimed to elucidate the mechanism underlying the effects of eHSP90α in pulmonary fibrosis by focusing on its link with endoplasmic reticulum (ER) stress. Our results showed that eHSP90α promoted lung fibroblast differentiation by activating ER stress. Treatment with the ER stress inhibitor tauroursodeoxycholate (TUDCA) or glucose-regulated protein 78 kDa (GRP78) depletion significantly abrogated the effect of eHSP90α on ER stress and fibroblast activation. In addition, eHSP90α induced ER stress in fibroblasts via the phosphoinositide-4,5-bisphosphate 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway, which could be blocked by the PI3K/AKT inhibitor LY294002, and blockade of eHSP90α by 1G6-D7 markedly inhibited ER stress in the model, indicating preventive and therapeutic applications. Intriguingly, we observed that TUDCA effectively reduced the secretion of eHSP90α in vitro and in vivo. In conclusion, this study shows that the interaction between eHSP90α and ER stress plays a crucial role in pulmonary fibrosis, indicating a positive feedback in lung fibroblasts. Targeting eHSP90α and alleviating fibroblast ER stress may be promising therapeutic approaches for pulmonary fibrosis. Frontiers Media S.A. 2021-08-23 /pmc/articles/PMC8420756/ /pubmed/34497513 http://dx.doi.org/10.3389/fphar.2021.708462 Text en Copyright © 2021 Zhang, Zhong, Liu, Chen, Lu, Zeng, Qiao, Huang, Wan, Li, Meng, Zou, Cai and Dong. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Zhang, Jinming
Zhong, Wenshan
Liu, Yuanyuan
Chen, Weimou
Lu, Ye
Zeng, Zhaojin
Qiao, Yujie
Huang, Haohua
Wan, Xuan
Li, Wei
Meng, Xiaojing
Zou, Fei
Cai, Shaoxi
Dong, Hangming
Extracellular HSP90α Interacts With ER Stress to Promote Fibroblasts Activation Through PI3K/AKT Pathway in Pulmonary Fibrosis
title Extracellular HSP90α Interacts With ER Stress to Promote Fibroblasts Activation Through PI3K/AKT Pathway in Pulmonary Fibrosis
title_full Extracellular HSP90α Interacts With ER Stress to Promote Fibroblasts Activation Through PI3K/AKT Pathway in Pulmonary Fibrosis
title_fullStr Extracellular HSP90α Interacts With ER Stress to Promote Fibroblasts Activation Through PI3K/AKT Pathway in Pulmonary Fibrosis
title_full_unstemmed Extracellular HSP90α Interacts With ER Stress to Promote Fibroblasts Activation Through PI3K/AKT Pathway in Pulmonary Fibrosis
title_short Extracellular HSP90α Interacts With ER Stress to Promote Fibroblasts Activation Through PI3K/AKT Pathway in Pulmonary Fibrosis
title_sort extracellular hsp90α interacts with er stress to promote fibroblasts activation through pi3k/akt pathway in pulmonary fibrosis
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420756/
https://www.ncbi.nlm.nih.gov/pubmed/34497513
http://dx.doi.org/10.3389/fphar.2021.708462
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