Mechanical ventilation induces diaphragmatic mitochondrial oxidant production resulting in mitochondrial damage and respiratory dysfunction

Abstract

Mechanical ventilation (MV) is a life saving intervention used in patients with acute respiratory failure. Unfortunately, prolonged MV results in diaphragmatic weakness which is an important contributor to the failure to wean patients from MV. We have shown that reactive oxygen species (ROS) play a critical role in diaphragmatic weakness following MV, but the pathways responsible for MV‐induced diaphragmatic ROS production remain unknown. We hypothesized that following MV diaphragmatic mitochondria produce higher rates of ROS resulting in mitochondrial oxidative damage and dysfunction. Our results support this hypothesis as mitochondria isolated from the diaphragm of MV rats possessed a lower respiratory control ratio compared to control. Further, MV diaphragmatic mitochondria produced higher rates of ROS in both state 3 and state 4 respiration. MV diaphragmatic mitochondria also exhibited higher levels of oxidative damage as indicated by increased lipid peroxidation and protein oxidation. Finally, our data also reveal that the activities of electron transport chain complex II, III, and IV are depressed in diaphragmatic mitochondria following MV. In summary, these results are consistent with the concept that diaphragmatic inactivity promotes an increase in mitochondrial ROS production resulting in mitochondrial oxidative damage and respiratory dysfunction.Supported by an NIH R01 awarded to SKP.