title: Oxidative stress is required for mechanical ventilation-induced protease activation in the diaphragm.
abstract: Prolonged mechanical ventilation (MV) results in diaphragmatic weakness due to fiber atrophy and contractile dysfunction. Recent work reveals that activation of the proteases calpain and caspase-3 is required for MV-induced diaphragmatic atrophy and contractile dysfunction. However, the mechanism(s) responsible for activation of these proteases remains unknown. To address this issue, we tested the hypothesis that oxidative stress is essential for the activation of calpain and caspase-3 in the diaphragm during MV. Cause-and-effect was established by prevention of MV-induced diaphragmatic oxidative stress using the antioxidant Trolox. Treatment of animals with Trolox prevented MV-induced protein oxidation and lipid peroxidation in the diaphragm. Importantly, the Trolox-mediated protection from MV-induced oxidative stress prevented the activation of calpain and caspase-3 in the diaphragm during MV. Furthermore, the avoidance of MV-induced oxidative stress not only averted the activation of these proteases but also rescued the diaphragm from MV-induced diaphragmatic myofiber atrophy and contractile dysfunction. Collectively, these findings support the prediction that oxidative stress is required for MV-induced activation of calpain and caspase-3 in the diaphragm and are consistent with the concept that antioxidant therapy can retard MV-induced diaphragmatic weakness.
authors.affiliation: Department of Applied Physiology and Kinesiology, University of Florida, PO Box 118205, Gainesville, FL 32611, USA. whiddenm@gmail.com
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Whidden
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Smuder
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Hudson
authors.forename: W Bradley
authors.initials: WB
authors.lastname: Nelson
authors.forename: Scott K
authors.initials: SK
authors.lastname: Powers
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001284:Atrophy; D002154:Calpain / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism*; D002839:Chromans / Q000494:pharmacology; D003964:Diaphragm / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D004558:Electric Stimulation; D004789:Enzyme Activation; D005260:Female; D007537:Isometric Contraction; D015227:Lipid Peroxidation; D008840:Microfilament Proteins / Q000378:metabolism; D018908:Muscle Weakness / Q000201:enzymology / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D018384:Oxidative Stress / Q000187:drug effects; D050050:Protein Carbonylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012121:Respiration, Artificial / Q000009:adverse effects*; D033921:Vesicular Transport Proteins / Q000378:metabolism
chemical_list: D000447:Aldehydes; D000975:Antioxidants; D002839:Chromans; D008840:Microfilament Proteins; C422208:Sptan1 protein, rat; D033921:Vesicular Transport Proteins; D002154:Calpain; C505410:Casp3 protein, rat; D053148:Caspase 3; C027576:4-hydroxy-2-nonenal; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid