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 cel...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(AEC2 s)in a time-dependent manner following multiple bleomycin-induced PF.Repeated injury of AEC2 s resulted in telomere shortening and triggered P21-dependent cell senescence.AEC2 s with elevated expression of P21 lost their self-renewal and differentiation abilities.In particular,elevated P21 not only induced cell cycle arrest in AEC2 s but also bound to P300 andβ-catenin and inhibited AEC2 differentiation by disturbing the P300-β-catenin interaction.Meanwhile,senescent AEC2 s 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.展开更多
基金supported by grants from National Key R&D Program of China(2017YFA0205400)National Natural Science Foundation of China(81773781 to Zhuowei Hu+4 种基金81503128 to Xiaoxi Lv)from CAMS Innovation Found for Medical Sciences(2016-I2M-1-007 to Zhuowei Hu,Fang Hua2016-I2M-1008 to Xiaoxi Lv2016-I2M-1-011 to Ke Li2016-I2M-3-008 to Bing Cui,Shanshan Liu,Jiaojiao Yu,and Jinmei Yu,China)。
文摘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(AEC2 s)in a time-dependent manner following multiple bleomycin-induced PF.Repeated injury of AEC2 s resulted in telomere shortening and triggered P21-dependent cell senescence.AEC2 s with elevated expression of P21 lost their self-renewal and differentiation abilities.In particular,elevated P21 not only induced cell cycle arrest in AEC2 s but also bound to P300 andβ-catenin and inhibited AEC2 differentiation by disturbing the P300-β-catenin interaction.Meanwhile,senescent AEC2 s 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.
