Ruxolitinib: A new hope for ventilator-induced diaphragm dysfunction

Area of Science:

• Biomedical Research
• Physiology
• Pharmacology

Background:

• Mechanical ventilation (MV) can cause ventilator-induced diaphragm dysfunction (VIDD), characterized by diaphragm weakness and atrophy.
• The Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway is implicated in VIDD pathogenesis.
• JAK/STAT inhibition has shown promise in mitigating chronic muscle wasting conditions.

Purpose of the Study:

• To investigate the therapeutic efficacy of Ruxolitinib, a JAK1/2 inhibitor, in treating ventilator-induced diaphragm dysfunction (VIDD).
• To explore the effects of Ruxolitinib on diaphragm muscle size, function, mitochondrial integrity, and protein modifications in a rat model of MV.

Main Methods:

• Rats underwent controlled mechanical ventilation (CMV) for 5 days, with or without daily Ruxolitinib administration.
• Diaphragm muscle size and specific force were measured.
• RNA sequencing, mitochondrial morphology, respirometry, and mass spectrometry were employed to assess molecular and cellular changes.

Main Results:

• CMV significantly reduced diaphragm size and force, increased P-STAT3, and impaired mitochondrial function and respiration.
• Ruxolitinib treatment increased animal survival, attenuated P-STAT3 upregulation, and preserved diaphragm size and specific force.
• Ruxolitinib maintained mitochondrial content and respiratory function, and reversed specific myosin post-translational modifications (PTMs) induced by ventilation.

Conclusions:

• Ruxolitinib administration preserved diaphragm function and enhanced survival in an experimental VIDD model.
• The functional benefits were linked to maintained mitochondrial health and reversed ventilator-induced myosin PTMs.
• These findings support the potential repurposing of Ruxolitinib for the clinical treatment of VIDD.