Cellular senescence contributes to mechanical ventilation-induced diaphragm dysfunction by upregulating p53...

Area of Science:

• Physiology
• Cell Biology
• Pathology

Background:

• Mechanical ventilation can lead to diaphragm atrophy and injury, impacting clinical outcomes.
• The precise mechanisms behind ventilation-induced diaphragm dysfunction (VIDD) remain unclear.
• This study investigates the potential involvement of cellular senescence in VIDD.

Purpose of the Study:

• To explore the role of cellular senescence in the development of ventilation-induced diaphragm dysfunction (VIDD).
• To elucidate the mechanisms underlying diaphragm injury caused by mechanical ventilation.

Main Methods:

• New Zealand rabbits were divided into control (spontaneously breathing) and mechanically ventilated (48h, V-ACV mode) groups.
• Diaphragm tissues were analyzed for sarcomere disruption, protein and mRNA expression (MAFbx, MuRF1, p53, p21), and senescence markers (SA-βGal, Pai1, MMP9).
• RNA-sequencing was employed to identify enriched senescence-associated genes.

Main Results:

• Mechanically ventilated rabbits showed significantly higher sarcomere disruption and diaphragm atrophy compared to controls.
• Expression of atrophy markers (MAFbx, MuRF1) and senescence markers (p53, p21, SA-βGal, Pai1, MMP9) were significantly upregulated in the ventilated group.
• RNA-seq analysis revealed a significant enrichment of senescence-associated genes in the mechanically ventilated group.

Conclusions:

• Mechanical ventilation for 48 hours induces significant diaphragm ultrastructural damage and atrophy in a rabbit model.
• p53-dependent cellular senescence is implicated in the pathogenesis of mechanical ventilation-induced diaphragm dysfunction.
• These findings suggest potential novel therapeutic targets for addressing VIDD.