Background: 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.
Objective: 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.
Design: 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).
Measurements and Main Results: 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.
Conclusions: 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.
From the Department of Applied Physiology and Kinesiology (SKP, MBH, WBN, EET, KM, ANK, AJS), University of Florida, Gainesville, FL; and Department of Pharmacology (HHS), Weill Cornell Medical College, New York, NY.
Supported, in part, by grant R01HL087839 from the National Institutes of Health (Bethesda, MD) awarded to Scott K. Powers.
Dr. Szeto consulted for Stealth Peptides (Newton Centre, MA) and holds equity interest and stock ownership with Stealth Peptides. Dr. Szeto also received a sponsored research grant from Stealth Peptides and has pending patents from the Cornell Research Foundation (Ithaca, NY). Dr. Szeto is the inventor of SS-31. The technology was licensed by the Cornell Research Foundation to Stealth Peptides for clinical development. The SS peptide technology has been licensed for commercial development by the Cornell Research Foundation, and both the Cornell Research Foundation and Dr. Szeto have financial interests. The remaining authors have not disclosed any potential conflicts of interest.
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