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Mitochondria-targeted antioxidants protect against mechanical ventilation-induced diaphragm weakness.

ABSTRACT: Mechanical ventilation is a life-saving intervention used to provide adequate pulmonary ventilation in patients suffering from respiratory failure. However, prolonged mechanical ventilation is associated with significant diaphragmatic weakness resulting from both myofiber atrophy and contractile dysfunction. Although several signaling pathways contribute to diaphragm weakness during mechanical ventilation, it is established that oxidative stress is required for diaphragmatic weakness to occur. Therefore, identifying the site(s) of mechanical ventilation- induced reactive oxygen species production in the diaphragm is important.These experiments tested the hypothesis that elevated mitochondrial reactive oxygen species emission is required for mechanical ventilation-induced oxidative stress, atrophy, and contractile dysfunction in the diaphragm.Cause and effect was determined by preventing mechanical ventilation-induced mitochondrial reactive oxygen species emission in the diaphragm of rats using a novel mitochondria-targeted antioxidant (SS-31).None.Compared to mechanically ventilated animals treated with saline, animals treated with SS-31 were protected against mechanical ventilation-induced mitochondrial dysfunction, oxidative stress, and protease activation in the diaphragm. Importantly, treatment of animals with the mitochondrial antioxidant also protected the diaphragm against mechanical ventilation-induced myofiber atrophy and contractile dysfunction.These results reveal that prevention of mechanical ventilation-induced increases in diaphragmatic mitochondrial reactive oxygen species emission protects the diaphragm from mechanical ventilation-induced diaphragmatic weakness. This important new finding indicates that mitochondria are a primary source of reactive oxygen species production in the diaphragm during prolonged mechanical ventilation. These results could lead to the development of a therapeutic intervention to impede mechanical ventilation-induced diaphragmatic weakness.

SUBMITTER: Powers SK

PROVIDER: S-EPMC4995067 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Mitochondria-targeted antioxidants protect against mechanical ventilation-induced diaphragm weakness.

Powers Scott K SK Hudson Matthew B MB Nelson W Bradley WB Talbert Erin E EE Min Kisuk K Szeto Hazel H HH Kavazis Andreas N AN Smuder Ashley J AJ

Critical care medicine 20110701 7

<h4>Background</h4>Mechanical ventilation is a life-saving intervention used to provide adequate pulmonary ventilation in patients suffering from respiratory failure. However, prolonged mechanical ventilation is associated with significant diaphragmatic weakness resulting from both myofiber atrophy and contractile dysfunction. Although several signaling pathways contribute to diaphragm weakness during mechanical ventilation, it is established that oxidative stress is required for diaphragmatic w ...[more]

PMID: 21460706

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Project description:ObjectivesAlthough mechanical ventilation is a life-saving measure for patients in respiratory failure, prolonged mechanical ventilation results in diaphragmatic weakness attributable to fiber atrophy and contractile dysfunction. Therefore, identifying the signaling pathways responsible for mechanical ventilation-induced diaphragmatic weakness is important. In this context, it is established that oxidative stress is required for mechanical ventilation-induced diaphragmatic weakness to occur. Numerous redox-sensitive signaling pathways exist in muscle including the transcription factor nuclear factor-κB. Although it has been suggested that nuclear factor-κB contributes to proteolytic signaling in inactivity-induced atrophy in locomotor muscles, the role that nuclear factor-κB plays in mechanical ventilation-induced diaphragmatic weakness is unknown. We tested the hypothesis that nuclear factor-κB activation plays a key signaling role in mechanical ventilation-induced diaphragmatic weakness and that oxidative stress is required for nuclear factor-κB activation.DesignCause and effect was determined by independently treating mechanically ventilated animals with either a specific nuclear factor-κB inhibitor (SN50) or a clinically relevant antioxidant (curcumin).Measurements and main resultsInhibition of nuclear factor-κB activity partially attenuated both mechanical ventilation-induced diaphragmatic atrophy and contractile dysfunction. Further, treatment with the antioxidant curcumin prevented mechanical ventilation-induced activation of nuclear factor-κB in the diaphragm and rescued the diaphragm from both mechanical ventilation-induced atrophy and contractile dysfunction.ConclusionsCollectively, these findings support the hypothesis that nuclear factor-κB activation plays a significant signaling role in mechanical ventilation-induced diaphragmatic weakness and that oxidative stress is an upstream activator of nuclear factor-κB. Finally, our results suggest that prevention of mechanical ventilation-induced oxidative stress in the diaphragm could be a useful clinical strategy to prevent or delay mechanical ventilation-induced diaphragmatic weakness.

Project description:BACKGROUND:Lung-protective ventilation (LPV) has been found to minimize the risk of ventilator-induced lung injury (VILI). However, whether LPV is able to diminish ventilator-induced diaphragm dysfunction (VIDD) remains unknown. This study was designed to test the hypothesis that LPV protects the diaphragm against VIDD. METHODS:Adult male Wistar rats received either conventional mechanical (tidal volume [VT]: 10 ml/kg, positive end-expiratory pressure [PEEP]: 2 cm H2O; CV group) or lung-protective (VT: 5 ml/kg, PEEP: 10 cm H2O; LPV group) ventilation for 12 h. Then, diaphragms and lungs were collected for biochemical and histological analyses. Transcriptome sequencing (RNA-seq) was performed to determine the differentially expressed genes in the diaphragms between groups. RESULTS:Our results suggested that LPV was associated with diminished pulmonary injuries and reduced oxidative stress compared with the effects of the CV strategy in rats. However, animals that received LPV showed increased protein degradation, decreased cross-sectional areas (CSAs) of myofibers, and reduced forces of the diaphragm compared with the same parameters in animals receiving CV (p < 0.05). In addition, the LPV group showed a higher level of oxidative stress in the diaphragm than the CV group (p < 0.05). Moreover, RNA-seq and western blots revealed that the peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC-1α), a powerful reactive oxygen species (ROS) inhibitor, was significantly downregulated in the LPV group compared with its expression in the CV group (p < 0.05). CONCLUSIONS:Compared with the CV strategy, the LPV strategy did not protect the diaphragm against VIDD in rats. In contrast, the LPV strategy worsened VIDD by inducing oxidative stress together with the downregulation of PGC-1α in the diaphragm. However, further studies are required to determine the roles of PGC-1α in ventilator-induced diaphragmatic oxidative stress.

Project description:Mechanical ventilation (MV) is a clinical tool providing adequate alveolar ventilation in patients that require respiratory support. Although a life-saving intervention for critically ill patients, prolonged MV results in the rapid development of inspiratory muscle weakness due to both diaphragmatic atrophy and contractile dysfunction; collectively known as "ventilator-induced diaphragm dysfunction" (VIDD). VIDD is a severe clinical problem because diaphragmatic weakness is a risk factor for difficulties in weaning patients from MV. Currently, no standard treatment to prevent VIDD exists. Nonetheless, growing evidence reveals that hydrogen sulfide (H2 S) possesses cytoprotective properties capable of protecting skeletal muscles against several hallmarks of VIDD, including oxidative damage, accelerated proteolysis, and mitochondrial damage. Therefore, we used an established animal model of MV to test the hypothesis that treatment with sodium sulfide (H2 S donor) will defend against VIDD. Our results confirm that sodium sulfide was sufficient to protect the diaphragm against both MV-induced fiber atrophy and contractile dysfunction. H2 S prevents MV-induced damage to diaphragmatic mitochondria as evidenced by protection against mitochondrial uncoupling. Moreover, treatment with sodium sulfide prevented the MV-induced activation of the proteases, calpain, and caspase-3 in the diaphragm. Taken together, these results support the hypothesis that treatment with a H2 S donor protects the diaphragm against VIDD. These outcomes provide the first evidence that H2 S has therapeutic potential to protect against MV-induced diaphragm weakness and to reduce difficulties in weaning patients from the ventilator. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Mechanical ventilation (MV) results in diaphragm atrophy and contractile dysfunction, known as ventilator-induced diaphragm dysfunction (VIDD). VIDD is important because diaphragm weakness is a risk factor for problems in weaning patients from MV. Currently, no accepted treatment exists to protect against VIDD. Growing evidence reveals that hydrogen sulfide (H2 S) donors protect skeletal muscle against ischemia-reperfusion-induced injury. Nonetheless, it is unknown if treatment with a H2 S donor can protect against VIDD. WHAT QUESTION DID THIS STUDY ADDRESS? Can treatment with an H2 S donor protect against VIDD? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? This study provides the first evidence that treatment with a H2 S donor protects against VIDD. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? These new findings provide the basis for further exploration of H2 S donors as a therapy to prevent VIDD and reduce the risk of problems in weaning patients from MV.

Project description:PurposeLimb intensive care unit (ICU)-acquired weakness (ICUAW) and ICU acquired diaphragm weakness (DW) occur frequently in mechanically ventilated (MV) patients; their coexistence in cooperative and uncooperative patients is unknown. This study was designed to (1) describe the co-occurrence of the two conditions (2) evaluate the impact of ICUAW and DW on the ventilator-free days (VFDs) at 28 days and weaning success, and (3) assess the correlation between maximal inspiratory pressure (MIP) and thickening fraction (TFdi) in patients with DW.MethodsThis prospective pilot study was conducted in a single-center on 73 critically ill MV patients. Muscle weakness was defined as a Medical Research Council score < 48 in cooperative patients or a bilateral mean simplified peroneal nerve test < 5.26 mV in uncooperative patients. Diaphragm dysfunction was defined as MIP < 30 cm H2O or as a TFdi < 29%. Weaning success was defined according to weaning according to a new definition (WIND).ResultsFifty-seven patients (78%) had ICUAW and 59 (81%) had DW. The coexistence of the two conditions occurred in 48 patients (65%), without association (χ2 = 1.06, p = 0.304). In the adjusted analysis, ICUAW was independently related to VFDs at 28-days (estimate difference 6 days, p = 0.016), and WIND (OR of 3.62 for having WIND different than short weaning), whereas DW was not. The linear mixed model showed a significant but weak correlation between MIP and TFdi (p < 0.001).ConclusionThis pilot study is the first to explore the coexistence of ICUAW and DW in both cooperative and uncooperative patients; a lack of association was found between DW and ICUAW when considering both cooperative and uncooperative patients. We found a strong correlation between ICUAW but not DW with the VFDs at 28 days and weaning success. A future larger study is warranted in order to confirm our results, and should also investigate the use of transdiaphragmatic twitch pressure measurement during bilateral anterior magnetic phrenic nerve stimulation for the diagnosis of DW.

Project description:Controlled mechanical ventilation (CMV) is associated with the development of diaphragm atrophy and contractile dysfunction, and respiratory muscle weakness is thought to contribute significantly to delayed weaning of patients. Therefore, therapeutic strategies for preventing these processes may have clinical benefit. The aim of the current study was to investigate the role of the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in CMV-mediated diaphragm wasting and weakness in rats. CMV-induced diaphragm atrophy and contractile dysfunction coincided with marked increases in STAT3 phosphorylation on both tyrosine 705 (Tyr705) and serine 727 (Ser727). STAT3 activation was accompanied by its translocation into mitochondria within diaphragm muscle and mitochondrial dysfunction. Inhibition of JAK signaling during CMV prevented phosphorylation of both target sites on STAT3, eliminated the accumulation of phosphorylated STAT3 within the mitochondria, and reversed the pathologic alterations in mitochondrial function, reduced oxidative stress in the diaphragm, and maintained normal diaphragm contractility. In addition, JAK inhibition during CMV blunted the activation of key proteolytic pathways in the diaphragm, as well as diaphragm atrophy. These findings implicate JAK/STAT3 signaling in the development of diaphragm muscle atrophy and dysfunction during CMV and suggest that the delayed extubation times associated with CMV can be prevented by inhibition of Janus kinase signaling.-Smith, I. J., Godinez, G. L., Singh, B. K., McCaughey, K. M., Alcantara, R. R., Gururaja, T., Ho, M. S., Nguyen, H. N., Friera, A. M., White, K. A., McLaughlin, J. R., Hansen, D., Romero, J. M., Baltgalvis, K. A., Claypool, M. D., Li, W., Lang, W., Yam, G. C., Gelman, M. S., Ding, R., Yung, S. L., Creger, D. P., Chen, Y., Singh, R., Smuder, A. J., Wiggs, M. P., Kwon, O.-S., Sollanek, K. J., Powers, S. K., Masuda, E. S., Taylor, V. C., Payan, D. G., Kinoshita, T., Kinsella, T. M. Inhibition of Janus kinase signaling during controlled mechanical ventilation prevents ventilation-induced diaphragm dysfunction.

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Mitochondria-targeted antioxidants protect against mechanical ventilation-induced diaphragm weakness.

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Mitochondria-targeted antioxidants protect against mechanical ventilation-induced diaphragm weakness.

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