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
Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Department of Dermatology and The Norris Comprehensive Cancer Centre, University of Southern California Keck Medical Centre, Los Angeles, CA, United States.
Front Pharmacol. 2021 Aug 23;12:708462. doi: 10.3389/fphar.2021.708462. eCollection 2021.
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 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 and . 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.
肺纤维化的特征是肺泡上皮细胞损伤、肺成纤维细胞增殖、分化以及细胞外基质（ECM）沉积。我们之前的研究表明，细胞外热休克蛋白90α（eHSP90α）通过激活丝裂原活化蛋白激酶（MAPK）信号通路促进肺纤维化。因此，用1G6-D7（一种选择性HSP90α单克隆抗体）拮抗eHSP90α可有效改善纤维化。本研究旨在通过关注eHSP90α与内质网（ER）应激的联系，阐明其在肺纤维化中的作用机制。我们的结果表明，eHSP90α通过激活ER应激促进肺成纤维细胞分化。用ER应激抑制剂牛磺熊去氧胆酸（TUDCA）或葡萄糖调节蛋白78 kDa（GRP78）耗竭处理可显著消除eHSP90α对ER应激和成纤维细胞活化的影响。此外，eHSP90α在成纤维细胞中诱导ER应激 磷酸肌醇-4,5-二磷酸3-激酶（PI3K）-蛋白激酶B（AKT）信号通路，该通路可被PI3K/AKT抑制剂LY294002阻断，而1G6-D7对eHSP90α的阻断显著抑制了模型中的ER应激，表明具有预防和治疗应用价值。有趣的是，我们观察到TUDCA有效降低了eHSP90α的分泌 以及 。总之，本研究表明eHSP90α与ER应激之间的相互作用在肺纤维化中起关键作用，表明在肺成纤维细胞中存在正反馈。靶向eHSP90α并减轻成纤维细胞ER应激可能是治疗肺纤维化的有前景的治疗方法。
