Dong Hangming, Luo Lishan, Zou Mengchen, Huang Chaowen, Wan Xuan, Hu Yahui, Le Yanqing, Zhao Haijin, Li Wei, Zou Fei, Cai Shaoxi
Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Department of Respiratory Medicine, Huizhou Municipal Central Hospital, Huizhou, China.
Am J Physiol Lung Cell Mol Physiol. 2017 Dec 1;313(6):L1006-L1015. doi: 10.1152/ajplung.00489.2016. Epub 2017 Aug 31.
Pulmonary fibrosis is characterized by lung fibroblast activation and ECM deposition and has a poor prognosis. Heat shock protein 90 (Hsp90) participates in organ fibrosis, and extracellular Hsp90α (eHsp90α) promotes fibroblast activation and migration. This study aimed to investigate whether a selective anti-Hsp90α monoclonal antibody, 1G6-D7, could attenuate lung fibrosis and whether 1G6-D7 presents a protective effect by inactivating the profibrotic pathway. Our results showed that eHsp90α was increased in mice with BLM-induced pulmonary fibrosis and that 1G6-D7 attenuated inflammation and collagen deposition in the lung. TGF-β1 induced eHsp90α secretion, concomitantly promoting HFL-1 activation and ECM synthesis. 1G6-D7-mediated inhibition of eHsp90α significantly blocked these effects, meanwhile inhibiting downstream profibrotic pathways such as ERK, Akt, and P38. Human recombinant (hr)Hsp90α mimicked the effects of TGF-β1, by activating profibrotic pathways and by upregulating LRP-1. Moreover, ERK inhibition effectively blocked the effect of (hr)Hsp90α. In conclusion, 1G6-D7 significantly protects against BLM-induced pulmonary fibrosis by ameliorating fibroblast activation and ECM production, which may be through blocking ERK signaling. Our results suggest a safer molecular therapy, 1G6-D7, in pulmonary fibrosis.
肺纤维化的特征是肺成纤维细胞活化和细胞外基质沉积，且预后较差。热休克蛋白90（Hsp90）参与器官纤维化，细胞外Hsp90α（eHsp90α）促进成纤维细胞活化和迁移。本研究旨在探讨选择性抗Hsp90α单克隆抗体1G6-D7是否能减轻肺纤维化，以及1G6-D7是否通过使促纤维化途径失活而发挥保护作用。我们的结果表明，博来霉素诱导的肺纤维化小鼠中eHsp90α增加，且1G6-D7减轻了肺部炎症和胶原沉积。转化生长因子-β1（TGF-β1）诱导eHsp90α分泌，同时促进人胚肺成纤维细胞系（HFL-1）活化和细胞外基质合成。1G6-D7介导的对eHsp90α的抑制显著阻断了这些作用，同时抑制了细胞外调节蛋白激酶（ERK）、蛋白激酶B（Akt）和P38等下游促纤维化途径。人重组（hr）Hsp90α通过激活促纤维化途径和上调低密度脂蛋白受体相关蛋白1（LRP-1）模拟了TGF-β1的作用。此外，ERK抑制有效阻断了（hr）Hsp90α的作用。总之，1G6-D7通过改善成纤维细胞活化和细胞外基质产生，显著保护小鼠免受博来霉素诱导的肺纤维化，这可能是通过阻断ERK信号实现的。我们的结果提示了一种在肺纤维化中更安全的分子疗法——1G6-D7。
