A missing piece of the puzzle in pulmonary fibrosis: anoikis resistance promotes fibroblast activation

Cell & Bioscience

Wei Wang¹  Shencun Fang¹  Juan Yin²  Xinxin Zhang²  Jie Huang²  Yan Liao²  Mengling Chen²  Jing Wang²  Sha Wang²  Jie Chao²  Wei Luo²  Jiawei Ding² 

[1] Department of Respiratory Medicine, Nanjing Chest Hospital, the Affiliated Brain Hospital of Nanjing Medical University;Jiangsu Provincial Key Laboratory of Critical Care Medicine, Zhongda Hospital, Department of Physiology, School of Medicine, Southeast University;

关键词: Anoikis;    ZC3H4;    Pulmonary fibrosis;    Fibroblast;    ECM;   

DOI  :  10.1186/s13578-022-00761-2

来源: DOAJ

【 摘 要 】

Abstract Background Pulmonary fibrosis initiates a pneumonic cascade that leads to fibroblast dysfunction characterized by excess proliferation. Anoikis is a physiological process that ensures tissue development and homeostasis. Researchers have not clearly determined whether disruption of anoikis is involved in pulmonary fibrosis. Results Here, we investigated the mechanism by which silica induces fibroblast activation via anoikis resistance and subsequent fibrosis. Anoikis of lung fibroblasts, alveolar epithelial cells and endothelial cells during the process of fibrosis was detected using CCK-8, western blot, cell count and flow cytometry (FCM) assays. Although the three cell types showed similar increases in proliferation, the expression of NTRK2, a marker of anoikis resistance, was upregulated specifically in fibroblasts, indicating the unique proliferation mechanism of fibroblasts in pulmonary fibrosis, which may be related to anoikis resistance. Furthermore, the CRISPR/Cas9 system was used to investigate the molecular mechanism of anoikis resistance; the SiO2-induced inflammatory response activated the MAPK/PI3K signaling pathway in lung fibroblasts and then induced the expression of the ZC3H4 protein, which specifically mediated anoikis resistance, followed by pulmonary fibrosis. Conclusions The current study revealed a specific pattern of fibroblast proliferation, and strategies targeting anoikis resistance may inhibit the pathological process of pulmonary fibrosis. This result provides a new approach for treating pulmonary fibrosis and new insights into the potential application of ZC3H4 in the development of novel therapeutic strategies for mitigating pulmonary fibrosis.

【 授权许可】

Unknown