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Mitochondria-targeted antioxidants protect against mechanical ventilation-induced diaphragm weakness
Journal article   Peer reviewed

Mitochondria-targeted antioxidants protect against mechanical ventilation-induced diaphragm weakness

Scott K Powers, Matthew B Hudson, W Bradley Nelson, Erin E Talbert, Kisuk Min, Hazel H Szeto, Andreas N Kavazis and Ashley J Smuder
Critical care medicine, Vol.39(7), pp.1749-1759
07/2011
DOI: 10.1097/CCM.0b013e3182190b62
PMCID: PMC4995067
PMID: 21460706

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Abstract

Mechanical ventilation is a life-saving intervention used to provide adequate pulmonary ventilation in patients suffering from respiratory failure. However, prolonged mechanical ventilation is associated with significant diaphragmatic weakness resulting from both myofiber atrophy and contractile dysfunction. Although several signaling pathways contribute to diaphragm weakness during mechanical ventilation, it is established that oxidative stress is required for diaphragmatic weakness to occur. Therefore, identifying the site(s) of mechanical ventilation- induced reactive oxygen species production in the diaphragm is important. These experiments tested the hypothesis that elevated mitochondrial reactive oxygen species emission is required for mechanical ventilation-induced oxidative stress, atrophy, and contractile dysfunction in the diaphragm. Cause and effect was determined by preventing mechanical ventilation-induced mitochondrial reactive oxygen species emission in the diaphragm of rats using a novel mitochondria-targeted antioxidant (SS-31). None. Compared to mechanically ventilated animals treated with saline, animals treated with SS-31 were protected against mechanical ventilation-induced mitochondrial dysfunction, oxidative stress, and protease activation in the diaphragm. Importantly, treatment of animals with the mitochondrial antioxidant also protected the diaphragm against mechanical ventilation-induced myofiber atrophy and contractile dysfunction. These results reveal that prevention of mechanical ventilation-induced increases in diaphragmatic mitochondrial reactive oxygen species emission protects the diaphragm from mechanical ventilation-induced diaphragmatic weakness. This important new finding indicates that mitochondria are a primary source of reactive oxygen species production in the diaphragm during prolonged mechanical ventilation. These results could lead to the development of a therapeutic intervention to impede mechanical ventilation-induced diaphragmatic weakness.
 Actins - metabolism Animals Calpain - metabolism Caspase 3 - metabolism Diaphragm - drug effects Diaphragm - metabolism Diaphragm - physiopathology Diaphragm - ultrastructure Female Hydrogen Peroxide - metabolism Mitochondria, Muscle - drug effects Mitochondria, Muscle - metabolism Mitochondria, Muscle - physiology Muscle Contraction - drug effects Muscle Contraction - physiology Muscle Fibers, Skeletal - drug effects Muscle Fibers, Skeletal - physiology Muscle Fibers, Skeletal - ultrastructure Muscle Proteins - metabolism Muscle Weakness - etiology Muscle Weakness - physiopathology Muscle Weakness - prevention & control Muscular Atrophy - etiology Muscular Atrophy - physiopathology Muscular Atrophy - prevention & control Oligopeptides - pharmacology Oxidative Stress - drug effects Oxidative Stress - physiology Rats Rats, Sprague-Dawley Respiration, Artificial - adverse effects SKP Cullin F-Box Protein Ligases - metabolism Tripartite Motif Proteins Ubiquitin-Protein Ligases - metabolism

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