Metformin attenuates fibroblast activation during pulmonary fibrosis by targeting S100A4 via AMPK-STAT3 axis.
Metformin attenuates fibroblast activation during pulmonary fibrosis by targeting S100A4 via AMPK-STAT3 axis.
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DOI：
10.3389/fphar.2023.1089812
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发表时间：
2023
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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作者：
成纤维细胞活化是特发性肺纤维化发生发展过程中的重要环节，而转化生长因子-β-1在成纤维细胞活化过程中起着关键的调节作用。已有报道二甲双胍(MET)通过调节转化生长因子-β-1诱导的成纤维细胞活化来减轻博莱霉素诱导的肺纤维化，但其机制仍需进一步研究。在本研究中，MET阻断了α-平滑肌肌动蛋白(α-SMA)在体内的积聚，并伴随着S100A4的表达和STAT3的磷酸化抑制，从而延缓了博莱姆治疗后肺纤维化的进展。S100A4在体外对成纤维细胞的激活起关键作用，siRNA下调S100A4的表达，下调转化生长因子-β1诱导的人胎肺成纤维细胞α-SMA的产生。重要的是，我们首次发现S100A4在成纤维细胞中的表达受STAT3的调节。STAT3磷酸化的有效小分子抑制剂他汀类药物能降低转化生长因子-β1诱导的HFL1细胞中S100A4的水平，同时减少α-SMA的产生。我们进一步发现，通过激活AMPK来抑制STAT3磷酸化的MET，在体外也通过靶向S100A4来抑制成纤维细胞的激活。综上所述，我们认为S100A4参与了转化生长因子-β1诱导的成纤维细胞活化的促纤维化作用，而MET通过下调S100A4的表达而对转化生长因子-β1诱导的成纤维细胞活化和博莱姆诱导的肺纤维化具有保护作用。这些结果为预防肺纤维化的临床策略提供了有用的线索。
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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