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.

细胞周期抑制剂 P21 与细胞衰老有关，并在肺损伤后的损伤修复过程中发挥重要作用。肺纤维化（PF）是一种以肺泡上皮细胞衰老为特征的纤维化肺部疾病。在本研究中，我们报告在多次博莱霉素诱导的 PF 后，P21 表达在肺泡上皮 2 型细胞 (AEC2s) 中以时间依赖性方式增加。AEC2 的反复损伤导致端粒缩短并触发 P21 依赖性细胞衰老。P21 表达升高的 AEC2 失去了自我更新和分化能力。特别是，升高的 P21 不仅诱导 AEC2 中的细胞周期停滞，而且还与 P300 和β-连环蛋白结合，并通过干扰 P300- β抑制 AEC2 分化。-连环蛋白相互作用。同时，衰老的 AEC2 通过释放促纤维化细胞因子触发肌成纤维细胞活化。P21的敲低恢复了 AEC2 介导的慢性 PF 小鼠肺泡再生。我们的研究结果揭示了在 PF 发展过程中 P21 介导的肺再生失败的机制，这为治疗纤维化肺病提供了一种潜在的策略。