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Published ahead of print on September 16, 2004, doi:10.1164/rccm.200407-939OC

Am. J. Respir. Crit. Care Med., Volume 170, Number 11, December 2004, 1179-1184

A more recent version of this article appeared on December 1, 2004
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Submitted on July 20, 2004
Accepted on September 10, 2004

Trolox Attenuates Mechanical Ventilation-induced Diaphragmatic Dysfunction and Proteolysis

Jenna L Betters1, David S Criswell1*, R. Andrew Shanely1, Darin Van Gammeren1, Darin Falk1, Keith C DeRuisseau1, Melissa Deering1, Tossaporn Yimlamai1, and Scott K Powers1

1 Departments of Applied Physiology and Kinesiology, and Physiology, Center for Exercise Science, University of Florida, Gainesville, FL, USA

* To whom correspondence should be addressed. E-mail: dcriswell{at}hhp.ufl.edu.

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% O2 for 12 hours. The antioxidant, Trolox, was intravenously infused in a subset of ventilated animals. Compared to acutely anesthetized, non-ventilated 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 to 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.
Key words: antioxidant, weaning, protein degradation, rat




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