| Mechanical ventilation (MV) is used to mechanically assist or replace spontaneous breathing in patients who cannot sustain sufficient alveolar ventilation. The withdrawal of MV from patients is referred to as "weaning" and problems in weaning patients from MV are common. Unfortunately, MV results in the development of diaphragmatic atrophy and contractile dysfunction that likely contribute to weaning difficulties. Importantly, oxidative stress has been critically linked to the signaling events responsible for the progression of MV-induced diaphragmatic atrophy. However, the sources of oxidants in the diaphragm during MV have not been fully elucidated. An intracellular enzyme, xanthine oxidase (XO), is capable of producing reactive oxygen species (ROS) in skeletal muscle and we hypothesized that XO plays a key role in MV-induced oxidative stress in the diaphragm. To test this postulate, we mechanically ventilated rats for 12 or 18 hours (MV) with a subset of animals that combined MV along with a XO inhibitor, oxypurinol (MVO). Indices of XO activity and protein, oxidative stress, contractile function, and atrophy were measured in the diaphragm following the experimental protocol. Our study reveals that XO activity is elevated in the diaphragm during MV and oxypurinol provides protection against oxidative injury and contractile dysfunction. Specifically, oxypurinol administration attenuated protein oxidation and lipid peroxidation in the diaphragm during MV. Further, XO inhibition attenuated MV-induced contractile dysfunction of the diaphragm at stimulation frequencies above 60 hertz at both 12 and 18 hours of MV. Together, these results reveal that XO-mediated production of oxidants is involved in MV-induced diaphragmatic oxidative stress and contractile dysfunction. |
