title: Trolox attenuates mechanical ventilation-induced diaphragmatic dysfunction and proteolysis.
abstract: Prolonged mechanical ventilation results in diaphragmatic oxidative injury, elevated proteolysis, fiber atrophy, and reduced force-generating capacity. We tested the hypothesis that antioxidant infusion during mechanical ventilation would function as an antioxidant to maintain redox balance within diaphragm muscle fibers and therefore prevent oxidative stress and subsequent proteolysis and contractile dysfunction. Sprague-Dawley rats were anesthetized, tracheostomized, and mechanically ventilated with 21% O(2) for 12 hours. The antioxidant Trolox was intravenously infused in a subset of ventilated animals. Compared with acutely anesthetized, nonventilated control animals, mechanical ventilation resulted in a significant reduction (-17%) in diaphragmatic maximal tetanic force. Importantly, Trolox completely attenuated this mechanical ventilation-induced diaphragmatic contractile deficit. Total diaphragmatic proteolysis was increased 105% in mechanical ventilation animals compared with controls. In contrast, diaphragmatic proteolysis did not differ between controls and mechanical ventilation-Trolox animals. Moreover, 20S proteasome activity in the diaphragm was elevated in the mechanical ventilation animals (+76%); Trolox treatment attenuated this mechanical ventilation-induced rise in protease activity. These results are consistent with the hypothesis that mechanical ventilation-induced oxidative stress is an important factor regulating mechanical ventilation-induced diaphragmatic proteolysis and contractile dysfunction. Our findings suggest that antioxidant therapy could be beneficial during prolonged mechanical ventilation.
authors.affiliation: Department of Applied Physiology and Kinesiology, Center for Exercise Science, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Jenna L
authors.initials: JL
authors.lastname: Betters
authors.forename: David S
authors.initials: DS
authors.lastname: Criswell
authors.forename: R Andrew
authors.initials: RA
authors.lastname: Shanely
authors.forename: Darin
authors.initials: D
authors.lastname: Van Gammeren
authors.forename: Darin
authors.initials: D
authors.lastname: Falk
authors.forename: Keith C
authors.initials: KC
authors.lastname: Deruisseau
authors.forename: Melissa
authors.initials: M
authors.lastname: Deering
authors.forename: Tossaporn
authors.initials: T
authors.lastname: Yimlamai
authors.forename: Scott K
authors.initials: SK
authors.lastname: Powers
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D002839:Chromans / Q000494:pharmacology* / Q000627:therapeutic use; D003964:Diaphragm / Q000187:drug effects* / Q000503:physiopathology; D005260:Female; D023421:Models, Animal; D009124:Muscle Proteins / Q000187:drug effects / Q000378:metabolism; D009135:Muscular Diseases / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects; D010447:Peptide Hydrolases / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012121:Respiration, Artificial / Q000009:adverse effects*
chemical_list: D000975:Antioxidants; D002839:Chromans; D009124:Muscle Proteins; D010447:Peptide Hydrolases; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid