Extracellular HSP90α Interacts With ER Stress to Promote Fibroblasts Activation Through PI3K/AKT Pathway in Pulmonary Fibrosis.
Extracellular HSP90α Interacts With ER Stress to Promote Fibroblasts Activation Through PI3K/AKT Pathway in Pulmonary Fibrosis.
复制标题
肺纤维化中细胞外 HSP90α 与 ER 应激相互作用，通过 PI3K/AKT 途径促进成纤维细胞活化
DOI：
10.3389/fphar.2021.708462
复制
发表时间：
2021
影响因子：
5.6
通讯作者：
Dong H
中科院分区：
文献类型：
--
作者：
Zhang J;Zhong W;Liu Y;Chen W;Lu Y;Zeng Z;Qiao Y;Huang H;Wan X;Li W;Meng X;Zou F;Cai S;Dong H
肺纤维化的特征在于肺泡上皮细胞损伤、肺成纤维细胞增殖、分化和细胞外基质（ECM）沉积。我们前期的研究表明，细胞外热休克蛋白90 α（eHSP 90 α）通过激活MAPK信号通路促进肺纤维化。因此，用1G 6-D 7（一种选择性HSP 90 α单克隆抗体）拮抗eHSP 90 α可以有效地改善纤维化。本研究旨在通过探讨eHSP 90 α与内质网应激的关系，阐明eHSP 90 α在肺纤维化中的作用机制。结果表明，eHSP 90 α通过激活内质网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盐（TUDCA）或葡萄糖调节蛋白78 kDa（GRP 78）耗竭处理显著消除了eHSP 90 α对ER应激和成纤维细胞活化的作用。此外，eHSP 90 α通过磷酸肌醇-4，5-二磷酸3-激酶（PI 3 K）-蛋白激酶B（AKT）信号通路诱导成纤维细胞的ER应激，该通路可被PI 3 K/AKT抑制剂LY 294002阻断，1G 6-D 7阻断eHSP 90 α可显著抑制该模型中的ER应激，提示其具有预防和治疗应用价值。有趣的是，我们观察到TUDCA在体外和体内有效地减少eHSP 90 α的分泌。本研究表明，eHSP 90 α与ER应激的相互作用在肺纤维化中起着重要作用，提示肺成纤维细胞中存在正反馈。以eHSP 90 α为靶点，减轻成纤维细胞内质网应激，可能是治疗肺纤维化的有效途径。
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 via 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 in vitro and in vivo. 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.
登录
查看更多内容
影响因子：
7.3
作者：
Kwon OC;Lee EJ;Chang EJ;Youn J;Ghang B;Hong S;Lee CK;Yoo B;Kim YG
通讯作者：
Kim YG
影响因子：
3.4
作者：
Guo J;Chang C;Li W
通讯作者：
Li W
影响因子：
4
作者：
Hosoi T;Nakashima M;Ozawa K
通讯作者：
Ozawa K
影响因子：
64.5
作者：
Cubillos-Ruiz JR;Bettigole SE;Glimcher LH
通讯作者：
Glimcher LH
影响因子：
28.5
作者：
Fan, Chi-Shuan;Chen, Li-Li;Huang, Tze-Sing
通讯作者：
Huang, Tze-Sing