The cell cycle inhibitor P21 promotes the development of pulmonary fibrosis by suppressing lung alveolar regeneration

• Published in: Acta pharmaceutica Sinica. B 2022-02, Vol.12 (2), p.735-746
• Main Authors: Lv, Xiaoxi, Liu, Chang, Liu, Shanshan, Li, Yunxuan, Wang, Wanyu, Li, Ke, Hua, Fang, Cui, Bing, Zhang, Xiaowei, Yu, Jiaojiao, Yu, Jinmei, Hu, ZhuoWei
• Format: Article
• Language: English
• Subjects: Alveolar epithelial type 2 cells; Alveolar regeneration; Bleomycin; Cell cycle arrest; Cell senescence; Original; P21; P300–β-catenin complex; Pulmonary fibrosis
• ISSN: 2211-3835; 2211-3843
• DOI: 10.1016/j.apsb.2021.07.015

The cell cycle inhibitor P21 has been implicated in cell senescence and plays an important role in the injury–repair process following lung injury. Pulmonary fibrosis (PF) is a fibrotic lung disorder characterized by cell senescence in lung alveolar epithelial cells. In this study, we report that P21 expression was increased in alveolar epithelial type 2 cells (AEC2s) in a time-dependent manner following multiple bleomycin-induced PF. Repeated injury of AEC2s resulted in telomere shortening and triggered P21-dependent cell senescence. AEC2s with elevated expression of P21 lost their self-renewal and differentiation abilities. In particular, elevated P21 not only induced cell cycle arrest in AEC2s but also bound to P300 and β-catenin and inhibited AEC2 differentiation by disturbing the P300–β-catenin interaction. Meanwhile, senescent AEC2s triggered myofibroblast activation by releasing profibrotic cytokines. Knockdown of P21 restored AEC2-mediated lung alveolar regeneration in mice with chronic PF. The results of our study reveal a mechanism of P21-mediated lung regeneration failure during PF development, which suggests a potential strategy for the treatment of fibrotic lung diseases. mBLM induced ROS and telomere shorten trigger P21-mediated senescence and promote the development of pulmonary fibrosis by inhibiting lung regeneration. [Display omitted]