Cellular senescence contributes to mechanical ventilation-induced diaphragm dysfunction by upregulating p53 signalling pathways.
BMC Pulm Med
; 23(1): 509, 2023 Dec 14.
Article
in En
| MEDLINE
| ID: mdl-38097957
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-ßGal 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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Respiration, Artificial
/
Diaphragm
Limits:
Animals
Language:
En
Journal:
BMC Pulm Med
/
BMC pulm. med
/
BMC pulmonary medicine
Year:
2023
Document type:
Article
Affiliation country:
Country of publication: