The cell cycle inhibitor P21 promotes the development of pulmonary fibrosis by suppressing lung alveolar regeneration.
10.1016/j.apsb.2021.07.015
- Author:
Xiaoxi LV
1
;
Chang LIU
1
;
Shanshan LIU
1
;
Yunxuan LI
1
;
Wanyu WANG
1
;
Ke LI
2
;
Fang HUA
1
;
Bing CUI
1
;
Xiaowei ZHANG
1
;
Jiaojiao YU
1
;
Jinmei YU
1
;
ZhuoWei HU
1
Author Information
1. Immunology and Cancer Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
2. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
- Publication Type:Journal Article
- Keywords:
Alveolar epithelial type 2 cells;
Alveolar regeneration;
Bleomycin;
Cell cycle arrest;
Cell senescence;
P21;
P300–β-catenin complex;
Pulmonary fibrosis
- From:
Acta Pharmaceutica Sinica B
2022;12(2):735-746
- CountryChina
- Language:English
-
Abstract:
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.
