Cellular senescence contributes to mechanical ventilation-induced diaphragm dysfunction by upregulating p53 signalling pathways
Abstract Background Mechanical ventilation can cause acute atrophy and injury in the diaphragm, which are related to adverse clinical results. However, the underlying mechanisms of ventilation-induced diaphragm dysfunction (VIDD) have not been well elucidated. The current study aimed to explore the...
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| Format: | Article |
| Language: | English |
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BMC
2023-12-01
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| Series: | BMC Pulmonary Medicine |
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| Online Access: | https://doi.org/10.1186/s12890-023-02662-7 |
| _version_ | 1797388532665286656 |
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| author | Weimin Shen Ye Jiang Ying Xu Xiaoli Qian Jianwei Jia Yuejia Ding Yuhan He Qing Pan Jinyang Zhuang Huiqing Ge Peifeng Xu |
| author_facet | Weimin Shen Ye Jiang Ying Xu Xiaoli Qian Jianwei Jia Yuejia Ding Yuhan He Qing Pan Jinyang Zhuang Huiqing Ge Peifeng Xu |
| author_sort | Weimin Shen |
| collection | DOAJ |
| description | Abstract Background Mechanical ventilation can cause acute atrophy and injury in the diaphragm, which are related to adverse clinical results. However, the underlying mechanisms of ventilation-induced diaphragm dysfunction (VIDD) have not been well elucidated. The current study aimed to explore the role of cellular senescence in VIDD. Methods A total of twelve New Zealand rabbits were randomly divided into 2 groups: (1) spontaneously breathing anaesthetized animals (the CON group) and (2) mechanically ventilated animals (for 48 h) in V-ACV mode (the MV group). Respiratory parameters were collected during ventilation. Diaphragm were collected for further analyses. Results Compared to those in the CON group, the percentage and density of sarcomere disruption in the MV group were much higher (p < 0.001, both). The mRNA expression of MAFbx and MuRF1 was upregulated in the MV group (p = 0.003 and p = 0.006, respectively). Compared to that in the CON group, the expression of MAFbx and MuRF1 detected by western blotting was also upregulated (p = 0.02 and p = 0.03, respectively). Moreover, RNA-seq showed that genes associated with senescence were remarkably enriched in the MV group. The mRNA expression of related genes was further verified by q-PCR (Pai1: p = 0.009; MMP9: p = 0.008). Transverse cross-sections of diaphragm myofibrils in the MV group showed more intensive positive staining of SA-βGal than those in the CON group. p53-p21 axis signalling was elevated in the MV group. The mRNA expression of p53 and p21 was significantly upregulated (p = 0.02 and p = 0.05, respectively). The western blot results also showed upregulation of p53 and p21 protein expression (p = 0.03 and p = 0.05, respectively). Moreover, the p21-positive staining in immunofluorescence and immunohistochemistry in the MV group was much more intense than that in the CON group (p < 0.001, both). Conclusions In a rabbit model, we demonstrated that mechanical ventilation in A/C mode for 48 h can still significantly induce ultrastructural damage and atrophy of the diaphragm. Moreover, p53-dependent senescence might play a role in mechanical ventilation-induced dysfunction. These findings might provide novel therapeutic targets for VIDD. |
| first_indexed | 2024-03-08T22:42:12Z |
| format | Article |
| id | doaj.art-4792be6a512745ee8738209ed7e11d53 |
| institution | Directory Open Access Journal |
| issn | 1471-2466 |
| language | English |
| last_indexed | 2024-03-08T22:42:12Z |
| publishDate | 2023-12-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Pulmonary Medicine |
| spelling | doaj.art-4792be6a512745ee8738209ed7e11d532023-12-17T12:05:38ZengBMCBMC Pulmonary Medicine1471-24662023-12-0123111110.1186/s12890-023-02662-7Cellular senescence contributes to mechanical ventilation-induced diaphragm dysfunction by upregulating p53 signalling pathwaysWeimin Shen0Ye Jiang1Ying Xu2Xiaoli Qian3Jianwei Jia4Yuejia Ding5Yuhan He6Qing Pan7Jinyang Zhuang8Huiqing Ge9Peifeng Xu10Department of Respiratory Care, Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang UniversityDepartment of Respiratory Care, Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang UniversityDepartment of Respiratory Care, Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang UniversityDepartment of Respiratory Care, Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang UniversityDepartment of Respiratory Care, Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang UniversityDepartment of Respiratory Care, Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang UniversityDepartment of Respiratory Care, Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang UniversityCollege of Information Engineering, Zhejiang University of TechnologyHuashan Hospital affiliated to Fudan UniversityDepartment of Respiratory Care, Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang UniversityDepartment of Respiratory Care, Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang UniversityAbstract Background Mechanical ventilation can cause acute atrophy and injury in the diaphragm, which are related to adverse clinical results. However, the underlying mechanisms of ventilation-induced diaphragm dysfunction (VIDD) have not been well elucidated. The current study aimed to explore the role of cellular senescence in VIDD. Methods A total of twelve New Zealand rabbits were randomly divided into 2 groups: (1) spontaneously breathing anaesthetized animals (the CON group) and (2) mechanically ventilated animals (for 48 h) in V-ACV mode (the MV group). Respiratory parameters were collected during ventilation. Diaphragm were collected for further analyses. Results Compared to those in the CON group, the percentage and density of sarcomere disruption in the MV group were much higher (p < 0.001, both). The mRNA expression of MAFbx and MuRF1 was upregulated in the MV group (p = 0.003 and p = 0.006, respectively). Compared to that in the CON group, the expression of MAFbx and MuRF1 detected by western blotting was also upregulated (p = 0.02 and p = 0.03, respectively). Moreover, RNA-seq showed that genes associated with senescence were remarkably enriched in the MV group. The mRNA expression of related genes was further verified by q-PCR (Pai1: p = 0.009; MMP9: p = 0.008). Transverse cross-sections of diaphragm myofibrils in the MV group showed more intensive positive staining of SA-βGal than those in the CON group. p53-p21 axis signalling was elevated in the MV group. The mRNA expression of p53 and p21 was significantly upregulated (p = 0.02 and p = 0.05, respectively). The western blot results also showed upregulation of p53 and p21 protein expression (p = 0.03 and p = 0.05, respectively). Moreover, the p21-positive staining in immunofluorescence and immunohistochemistry in the MV group was much more intense than that in the CON group (p < 0.001, both). Conclusions In a rabbit model, we demonstrated that mechanical ventilation in A/C mode for 48 h can still significantly induce ultrastructural damage and atrophy of the diaphragm. Moreover, p53-dependent senescence might play a role in mechanical ventilation-induced dysfunction. These findings might provide novel therapeutic targets for VIDD.https://doi.org/10.1186/s12890-023-02662-7Mechanical ventilationDiaphragm dysfunctionCellular senescencep53-p21 axis |
| spellingShingle | Weimin Shen Ye Jiang Ying Xu Xiaoli Qian Jianwei Jia Yuejia Ding Yuhan He Qing Pan Jinyang Zhuang Huiqing Ge Peifeng Xu Cellular senescence contributes to mechanical ventilation-induced diaphragm dysfunction by upregulating p53 signalling pathways BMC Pulmonary Medicine Mechanical ventilation Diaphragm dysfunction Cellular senescence p53-p21 axis |
| title | Cellular senescence contributes to mechanical ventilation-induced diaphragm dysfunction by upregulating p53 signalling pathways |
| title_full | Cellular senescence contributes to mechanical ventilation-induced diaphragm dysfunction by upregulating p53 signalling pathways |
| title_fullStr | Cellular senescence contributes to mechanical ventilation-induced diaphragm dysfunction by upregulating p53 signalling pathways |
| title_full_unstemmed | Cellular senescence contributes to mechanical ventilation-induced diaphragm dysfunction by upregulating p53 signalling pathways |
| title_short | Cellular senescence contributes to mechanical ventilation-induced diaphragm dysfunction by upregulating p53 signalling pathways |
| title_sort | cellular senescence contributes to mechanical ventilation induced diaphragm dysfunction by upregulating p53 signalling pathways |
| topic | Mechanical ventilation Diaphragm dysfunction Cellular senescence p53-p21 axis |
| url | https://doi.org/10.1186/s12890-023-02662-7 |
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