The cell cycle inhibitor P21 promotes the development of pulmonary fibrosis by suppressing lung alveolar regeneration
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 P2...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-02-01
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| Series: | Acta Pharmaceutica Sinica B |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383521002641 |
| _version_ | 1819279327256117248 |
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| author | Xiaoxi Lv Chang Liu Shanshan Liu Yunxuan Li Wanyu Wang Ke Li Fang Hua Bing Cui Xiaowei Zhang Jiaojiao Yu Jinmei Yu ZhuoWei Hu |
| author_facet | Xiaoxi Lv Chang Liu Shanshan Liu Yunxuan Li Wanyu Wang Ke Li Fang Hua Bing Cui Xiaowei Zhang Jiaojiao Yu Jinmei Yu ZhuoWei Hu |
| author_sort | Xiaoxi Lv |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-24T00:26:08Z |
| format | Article |
| id | doaj.art-6f83f89dce9748c186894e2e0b77c552 |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-12-24T00:26:08Z |
| publishDate | 2022-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-6f83f89dce9748c186894e2e0b77c5522022-12-21T17:24:25ZengElsevierActa Pharmaceutica Sinica B2211-38352022-02-01122735746The cell cycle inhibitor P21 promotes the development of pulmonary fibrosis by suppressing lung alveolar regenerationXiaoxi Lv0Chang Liu1Shanshan Liu2Yunxuan Li3Wanyu Wang4Ke Li5Fang Hua6Bing Cui7Xiaowei Zhang8Jiaojiao Yu9Jinmei Yu10ZhuoWei Hu11Immunology 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; Corresponding authors. Tel./fax: +86 10 83165034.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; Drug Clinical Trial Institution, Children's Hospital, Capital Institute of Pediatrics, Beijing 100020, ChinaImmunology 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, ChinaImmunology 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, ChinaImmunology 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, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, ChinaImmunology 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, ChinaImmunology 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, ChinaImmunology 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, ChinaImmunology 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, ChinaImmunology 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, ChinaImmunology 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; Corresponding authors. Tel./fax: +86 10 83165034.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.http://www.sciencedirect.com/science/article/pii/S2211383521002641P21Cell senescenceAlveolar epithelial type 2 cellsPulmonary fibrosisAlveolar regenerationBleomycin |
| spellingShingle | Xiaoxi Lv Chang Liu Shanshan Liu Yunxuan Li Wanyu Wang Ke Li Fang Hua Bing Cui Xiaowei Zhang Jiaojiao Yu Jinmei Yu ZhuoWei Hu The cell cycle inhibitor P21 promotes the development of pulmonary fibrosis by suppressing lung alveolar regeneration Acta Pharmaceutica Sinica B P21 Cell senescence Alveolar epithelial type 2 cells Pulmonary fibrosis Alveolar regeneration Bleomycin |
| title | The cell cycle inhibitor P21 promotes the development of pulmonary fibrosis by suppressing lung alveolar regeneration |
| title_full | The cell cycle inhibitor P21 promotes the development of pulmonary fibrosis by suppressing lung alveolar regeneration |
| title_fullStr | The cell cycle inhibitor P21 promotes the development of pulmonary fibrosis by suppressing lung alveolar regeneration |
| title_full_unstemmed | The cell cycle inhibitor P21 promotes the development of pulmonary fibrosis by suppressing lung alveolar regeneration |
| title_short | The cell cycle inhibitor P21 promotes the development of pulmonary fibrosis by suppressing lung alveolar regeneration |
| title_sort | cell cycle inhibitor p21 promotes the development of pulmonary fibrosis by suppressing lung alveolar regeneration |
| topic | P21 Cell senescence Alveolar epithelial type 2 cells Pulmonary fibrosis Alveolar regeneration Bleomycin |
| url | http://www.sciencedirect.com/science/article/pii/S2211383521002641 |
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