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Metformin attenuates fibroblast activation during pulmonary fibrosis by targeting S100A4 via AMPK-STAT3 axis

Fibroblasts activation is a crucial process for development of fibrosis during idiopathic pulmonary fibrosis pathogenesis, and transforming growth factor (TGF)-β1 plays a key regulatory role in fibroblast activation. It has been reported that metformin (MET) alleviated bleomycin (BLM)-induced pulmon...

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Autores principales: Ji, Huimin, Dong, Hongliang, Lan, Yuejiao, Bi, Yuqian, Gu, Xuan, Han, Yongyue, Yang, Chongyang, Cheng, Minghan, Gao, Jian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9936158/
https://www.ncbi.nlm.nih.gov/pubmed/36817136
http://dx.doi.org/10.3389/fphar.2023.1089812
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author Ji, Huimin
Dong, Hongliang
Lan, Yuejiao
Bi, Yuqian
Gu, Xuan
Han, Yongyue
Yang, Chongyang
Cheng, Minghan
Gao, Jian
author_facet Ji, Huimin
Dong, Hongliang
Lan, Yuejiao
Bi, Yuqian
Gu, Xuan
Han, Yongyue
Yang, Chongyang
Cheng, Minghan
Gao, Jian
author_sort Ji, Huimin
collection PubMed
description Fibroblasts activation is a crucial process for development of fibrosis during idiopathic pulmonary fibrosis pathogenesis, and transforming growth factor (TGF)-β1 plays a key regulatory role in fibroblast activation. It has been reported that metformin (MET) alleviated bleomycin (BLM)-induced pulmonary fibrosis (PF) by regulating TGF-β1-induced fibroblasts activation, but the underlying mechanisms still deserve further investigations. In this study, MET blocked α-smooth muscle actin (α-SMA) accumulation in vivo accompanied with S100A4 expression and STAT3 phosphorylation inhibition, resulting in attenuating the progression of lung fibrosis after BLM administration. We determined that S100A4 plays critical roles in fibroblasts activation in vitro, evidenced by siRNA knockdown of S100A4 expression downregulated TGF-β1 induced α-SMA production in Human fetal lung fibroblast (HFL1) cells. Importantly, we found for the first time that the expression of S100A4 in fibroblasts was regulated by STAT3. Stattic, an effective small molecule inhibitor of STAT3 phosphorylation, reduced S100A4 level in TGF-β1- treated HFL1 cells accompanied with less α-SMA production. We further found that MET, which inhibits STAT3 phosphorylation by AMPK activation, also inhibits fibroblasts activation by targeting S100A4 in vitro. Together all these results, we conclude that S100A4 contributes to TGF-β1- induced pro-fibrogenic function in fibroblasts activation, and MET was able to protect against TGF-β1-induced fibroblasts activation and BLM-induced PF by down-regulating S100A4 expression through AMPK-STAT3 axis. These results provide a useful clue for a clinical strategy to prevent PF.
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spelling pubmed-99361582023-02-18 Metformin attenuates fibroblast activation during pulmonary fibrosis by targeting S100A4 via AMPK-STAT3 axis Ji, Huimin Dong, Hongliang Lan, Yuejiao Bi, Yuqian Gu, Xuan Han, Yongyue Yang, Chongyang Cheng, Minghan Gao, Jian Front Pharmacol Pharmacology Fibroblasts activation is a crucial process for development of fibrosis during idiopathic pulmonary fibrosis pathogenesis, and transforming growth factor (TGF)-β1 plays a key regulatory role in fibroblast activation. It has been reported that metformin (MET) alleviated bleomycin (BLM)-induced pulmonary fibrosis (PF) by regulating TGF-β1-induced fibroblasts activation, but the underlying mechanisms still deserve further investigations. In this study, MET blocked α-smooth muscle actin (α-SMA) accumulation in vivo accompanied with S100A4 expression and STAT3 phosphorylation inhibition, resulting in attenuating the progression of lung fibrosis after BLM administration. We determined that S100A4 plays critical roles in fibroblasts activation in vitro, evidenced by siRNA knockdown of S100A4 expression downregulated TGF-β1 induced α-SMA production in Human fetal lung fibroblast (HFL1) cells. Importantly, we found for the first time that the expression of S100A4 in fibroblasts was regulated by STAT3. Stattic, an effective small molecule inhibitor of STAT3 phosphorylation, reduced S100A4 level in TGF-β1- treated HFL1 cells accompanied with less α-SMA production. We further found that MET, which inhibits STAT3 phosphorylation by AMPK activation, also inhibits fibroblasts activation by targeting S100A4 in vitro. Together all these results, we conclude that S100A4 contributes to TGF-β1- induced pro-fibrogenic function in fibroblasts activation, and MET was able to protect against TGF-β1-induced fibroblasts activation and BLM-induced PF by down-regulating S100A4 expression through AMPK-STAT3 axis. These results provide a useful clue for a clinical strategy to prevent PF. Frontiers Media S.A. 2023-02-03 /pmc/articles/PMC9936158/ /pubmed/36817136 http://dx.doi.org/10.3389/fphar.2023.1089812 Text en Copyright © 2023 Ji, Dong, Lan, Bi, Gu, Han, Yang, Cheng and Gao. 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
Ji, Huimin
Dong, Hongliang
Lan, Yuejiao
Bi, Yuqian
Gu, Xuan
Han, Yongyue
Yang, Chongyang
Cheng, Minghan
Gao, Jian
Metformin attenuates fibroblast activation during pulmonary fibrosis by targeting S100A4 via AMPK-STAT3 axis
title Metformin attenuates fibroblast activation during pulmonary fibrosis by targeting S100A4 via AMPK-STAT3 axis
title_full Metformin attenuates fibroblast activation during pulmonary fibrosis by targeting S100A4 via AMPK-STAT3 axis
title_fullStr Metformin attenuates fibroblast activation during pulmonary fibrosis by targeting S100A4 via AMPK-STAT3 axis
title_full_unstemmed Metformin attenuates fibroblast activation during pulmonary fibrosis by targeting S100A4 via AMPK-STAT3 axis
title_short Metformin attenuates fibroblast activation during pulmonary fibrosis by targeting S100A4 via AMPK-STAT3 axis
title_sort metformin attenuates fibroblast activation during pulmonary fibrosis by targeting s100a4 via ampk-stat3 axis
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9936158/
https://www.ncbi.nlm.nih.gov/pubmed/36817136
http://dx.doi.org/10.3389/fphar.2023.1089812
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