Extracellular HSP90α promotes cellular senescence by modulating TGF‐β signaling in pulmonary fibrosis
Extracellular HSP90α promotes cellular senescence by modulating TGF‐β signaling in pulmonary fibrosis
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DOI：
10.1096/fj.202200406rr
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发表时间：
2022-07
期刊：
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通讯作者：
W. Zhong;Weimou Chen;Yuanyuan Liu;Jinming Zhang;Ye Lu;X. Wan;Y. Qiao;Haohua Huang;Zhaojin Zeng;Wei Li;Xiaojing Meng;Hai-Jin Zhao;M. Zou;S. Cai;H. Dong
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文献类型：
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作者：
W. Zhong;Weimou Chen;Yuanyuan Liu;Jinming Zhang;Ye Lu;X. Wan;Y. Qiao;Haohua Huang;Zhaojin Zeng;Wei Li;Xiaojing Meng;Hai-Jin Zhao;M. Zou;S. Cai;H. Dong
近年来的研究表明，细胞外热休克蛋白90α（eHSP 90 α）促进肺纤维化，但其机制尚不清楚。衰老，特别是细胞衰老，是特发性肺纤维化（IPF）的关键风险因素。本研究旨在探讨eHSP 90 α在IPF细胞衰老中的作用。我们的研究结果发现，eHSP 90 α在博莱霉素（BLM）诱导的小鼠中上调，这与衰老标志物的表达相关。这种eHSP 90 α的增加介导了成纤维细胞衰老并促进了线粒体功能障碍。eHSP 90 α通过SMAD复合物的磷酸化激活TGF-β信号传导。SMAD复合物与p53和p21启动子的结合触发了它们的转录。在体内，用1G 6-D 7（一种特异性eHSP 90 α抗体）阻断老年小鼠中的eHSP 90 α可减轻BLM诱导的肺纤维化。我们的研究结果阐明了eHSP 90 α诱导细胞衰老的关键机制，为衰老相关的纤维化干预提供了框架。
Recent findings suggest that extracellular heat shock protein 90α (eHSP90α) promotes pulmonary fibrosis, but the underlying mechanisms are not well understood. Aging, especially cellular senescence, is a critical risk factor for idiopathic pulmonary fibrosis (IPF). Here, we aim to investigate the role of eHSP90α on cellular senescence in IPF. Our results found that eHSP90α was upregulated in bleomycin (BLM)‐induced mice, which correlated with the expression of senescence markers. This increase in eHSP90α mediated fibroblast senescence and facilitated mitochondrial dysfunction. eHSP90α activated TGF‐β signaling through the phosphorylation of the SMAD complex. The SMAD complex binding to p53 and p21 promoters triggered their transcription. In vivo, the blockade of eHSP90α with 1G6‐D7, a specific eHSP90α antibody, in old mice attenuated the BLM‐induced lung fibrosis. Our findings elucidate a crucial mechanism underlying eHSP90α‐induced cellular senescence, providing a framework for aging‐related fibrosis interventions.