Acute hypoxia-induced diaphragm dysfunction is prevented by antioxidant pre-treatment

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dc.contributor.advisor O'Halloran, Ken D. en
dc.contributor.advisor Mackrill, John en O'Leary, Andrew J. 2017-04-27T10:51:48Z 2017-04-27T10:51:48Z 2016 2016
dc.identifier.citation O'Leary, A. J. 2016. Acute hypoxia-induced diaphragm dysfunction is prevented by antioxidant pre-treatment. PhD Thesis, University College Cork. en
dc.identifier.endpage 237 en
dc.description.abstract Diaphragm weakness is a strong predictor of poor outcome in patients. Acute hypoxia is a feature of respiratory conditions such as acute respiratory distress syndrome and ventilator-associated lung injury. However, the effects of acute hypoxia on the diaphragm are largely unknown despite the potential clinical relevance. C57BL6/J mice were exposed to 8hr of hypoxia (FiO2 = 0.10) or normoxia. A separate group of mice were administered N-acetyl cysteine (NAC; 200mg/kg, I.P.) immediately prior to acute hypoxia exposure. Ventilation was assessed using whole-body plethysmography. O2 consumption and CO2 production were measured as indices of metabolism. Diaphragm muscle contractile performance was determined ex-vivo. Gene expression was examined at 1, 4, and 8 hrs using qRT-PCR. Protein/phosphoprotein content was assessed using a sandwich immunoassay. Proteasome activity was measured using a spectrophotometric assay. Acute hypoxia decreased diaphragm force and fatigue. Ventilation during acute hypoxia was initially increased during the first 10 minutes, but quickly returned to normoxic levels for the duration of gas exposure. Metabolism was reduced by acute hypoxia, and gene expression driving mitochondrial uncoupling was increased. Acute hypoxia increased atrophic signalling, but not proteasome activity. Acute hypoxia increased hypertrophic and hypoxia protein signalling. NAC pre-treatment prevented the acute hypoxia-induced diaphragm weakness. Diaphragm weakness is reported in mechanically ventilated patients, which is primarily attributed to inactivity of the muscle, although this is controversial. The potential role of hypoxia in the development and/or exacerbation of ICU-related weakness is unclear. These data reveals that acute hypoxia is sufficient to cause diaphragm muscle weakness, likely relates to hypoxic stress. Muscle weakness was prevented by antioxidant supplementation, independent of the hypoxia-induced hypometabolic state. These findings highlight a potentially critical role for hypoxia in diaphragm muscle dysfunction observed in patients with acute respiratory diseases, and the potential benefits of NAC in preventing acute hypoxia-induced diaphragm dysfunction. en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2016, Andrew James O'Leary. en
dc.rights.uri en
dc.subject Diaphragm en
dc.subject Hypoxia en
dc.subject Weakness en
dc.subject Muscle en
dc.subject NAC en
dc.subject Antioxidant en
dc.subject Oxidative stress en
dc.subject ROS en
dc.title Acute hypoxia-induced diaphragm dysfunction is prevented by antioxidant pre-treatment en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD (Medicine and Health) en
dc.internal.availability Full text available en No embargo required en
dc.description.version Accepted Version
dc.contributor.funder Physiology, College of Medicine and Health, University College Cork en
dc.contributor.funder Strategic Research Fund, University College Cork en
dc.description.status Not peer reviewed en Medicine en Physiology en
dc.check.type No Embargo Required
dc.check.reason No embargo required en
dc.check.opt-out No en
dc.thesis.opt-out false
dc.check.embargoformat Not applicable en
dc.internal.conferring Summer 2017 en

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© 2016, Andrew James O'Leary. Except where otherwise noted, this item's license is described as © 2016, Andrew James O'Leary.
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