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Mechanical ventilation reduces rat diaphragm blood flow and impairs oxygen delivery and uptake.

ABSTRACT: Although mechanical ventilation is a life-saving intervention in patients suffering from respiratory failure, prolonged mechanical ventilation is often associated with numerous complications including problematic weaning. In contracting skeletal muscle, inadequate oxygen supply can limit oxidative phosphorylation resulting in muscular fatigue. However, whether prolonged mechanical ventilation results in decreased diaphragmatic blood flow and induces an oxygen supply-demand imbalance in the diaphragm remains unknown.We tested the hypothesis that prolonged controlled mechanical ventilation results in a time-dependent reduction in rat diaphragmatic blood flow and microvascular PO2 and that prolonged mechanical ventilation would diminish the diaphragm's ability to increase blood flow in response to muscular contractions.Compared to 30 mins of mechanical ventilation, 6 hrs of mechanical ventilation resulted in a 75% reduction in diaphragm blood flow (via radiolabeled microspheres), which did not occur in the intercostal muscle or high-oxidative hindlimb muscle (e.g., soleus). There was also a time-dependent decline in diaphragm microvascular PO2 (via phosphorescence quenching). Further, contrary to 30 mins of mechanical ventilation, 6 hrs of mechanical ventilation significantly compromised the diaphragm's ability to increase blood flow during electrically-induced contractions, which resulted in a ~80% reduction in diaphragm oxygen uptake. In contrast, 6 hrs of spontaneous breathing in anesthetized animals did not alter diaphragm blood flow or the ability to augment flow during electrically-induced contractions.These new and important findings reveal that prolonged mechanical ventilation results in a time-dependent decrease in the ability of the diaphragm to augment blood flow to match oxygen demand in response to contractile activity and could be a key contributing factor to difficult weaning. Although additional experiments are required to confirm, it is tempting to speculate that this ventilator-induced decline in diaphragmatic oxygenation could promote a hypoxia-induced generation of reactive oxygen species in diaphragm muscle fibers and contribute to ventilator-induced diaphragmatic atrophy and contractile dysfunction.

SUBMITTER: Davis RT

PROVIDER: S-EPMC3455118 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Mechanical ventilation reduces rat diaphragm blood flow and impairs oxygen delivery and uptake.

Davis Robert T RT Bruells Christian S CS Stabley John N JN McCullough Danielle J DJ Powers Scott K SK Behnke Bradley J BJ

Critical care medicine 20121001 10

<h4>Objectives</h4>Although mechanical ventilation is a life-saving intervention in patients suffering from respiratory failure, prolonged mechanical ventilation is often associated with numerous complications including problematic weaning. In contracting skeletal muscle, inadequate oxygen supply can limit oxidative phosphorylation resulting in muscular fatigue. However, whether prolonged mechanical ventilation results in decreased diaphragmatic blood flow and induces an oxygen supply-demand imb ...[more]

PMID: 22846782

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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:SUMOylation is a key post-translational modification that regulates crucial cellular functions and pathological processes. It has emerged as a fundamental route that may drive different steps of human diseases. Indeed, alteration in expression or activity of one of the different SUMO pathway components may completely subvert cellular properties through fine-tuning modulation of protein(s) involved in cellular/tissue pathways, leading to alter cell proliferation, tissue regeneration, apoptosis resistance and metastatic potential. What is SUMOylation? SUMO, the Small Ubiquitin-like Modifier is a 97-amino acid protein that can be covalently attached to lysine residues on target proteins via an enzymatic cascade reaction named SUMOylation. SUMOylation requires an E1 (hetero-dimer SUMO-activating, SAE1/2), E2 (SUMO-specific conjugating, Ubc9), and, in most cases, E3 (SUMO ligase, PIASs) enzymes. There are four reported SUMO paralogues, SUMO-1 to SUMO-4, present in mammalian. All SUMO paralogues are transiently and reversibly conjugated to substrate proteins by the same enzymatic machinery but they can modify distinct targets although some proteins can be SUMOylated by either SUMO-1 or SUMO-2/3. The modifiers are expressed as immature peptides that must be cleaved prior to conjugation. This is carried out by isopeptidases, known as SENPs or SUMO specific proteases. The cleavage generates a C-terminal carboxyl group, SUMO-Gly-Gly, that will be attached via an isopeptide bond, formed between the epsilon-amino group of a Lys residue in the consensus sequence in target proteins designated ΨKxD/E, where Ψ is a large hydrophobic residue, K is the target lysine (Lys) and D/E are acidic residues. SUMO-2 and -3 have the ability to form poly-SUMO chains by covalent linkage of the C-terminal Gly-Gly residue to the internal Lys residue of their N-terminal consensus sequence motif. SUMO-1 lacks this consensus site and is unable to form chains but may act as a polySUMO chain terminator. SUMO-4 remains enigmatic since it has a restricted tissue distribution and may be unable to SUMOylate substrate proteins due to a proline residue that appears to prevent its maturation and conjugation. Heterodimeric activating enzyme E1 triggers SUMO proteins in an ATP-dependent way and transfers activated SUMO to a conserved catalytic cysteine in the conjugation enzyme E2. Ubc9, the only E2 identified delivers SUMO protein directly to the substrates. Ubc9 alone is sufficient for conjugation and ligation of the SUMO moiety to the substrates. However, the presence of SUMOylation E3 ligases, including the PIAS family, RanBP2, Polycomb2, TOPORS, TRAF7 and mitochondrial-anchored protein ligase (MPAL), stimulates the conjugation efficiency by promoting poly-SUMO chain formation and/or introducing additional SUMO acceptor sites. Despite being a covalent protein modification, SUMOylation is readily reversible due to the protease activity of SUMO specific deSUMOylation enzymes, SENPs. These enzymes exhibit specifically between the SUMO paralogues and have distinct subnuclear and subcellular localization patterns. Seven isoforms are known, including SENP1, SENP2, SENP3, SENP6 and SENP7. The SENPs contain distinct N-terminal domains that regulate their cellular localization, suggesting that each SENP may have a distinct set of substrates. In the last decade, the PTM with SUMO has emerged as a central regulatory mechanism for the control of cellular functions, including developmental and differentiation processes. However most of the studies have been performed on single eukaryotic cells from yeast to primary and model cells. The involvement of SUMOylation processes in regulating activity, function development and/or disorder in a more complex system like differentiated tissues (i.e: brain and cardiac muscle) is just emerging. At present, there is a completely lack of information regarding the functional significance of SUMOylation in skeletal muscle differentiation, regulation and diseases. Using a unique experimental Intensive Care Unit (ICU) rat model allowing long-term MV, diaphragm muscles were collected in rats control and exposed to controlled MV (CMV) for durations varying between 1 and 10 days. Endogenous SUMOylated diaphragm proteins were identified by mass-spectrometry and validated with in-vitro SUMOylation systems. Contractile, calcium regulator and mitochondrial proteins were of specific interest due to their putative involvement in VIDD. Differences were observed in the abundance of SUMOylated proteins between glycolytic and oxidative muscle fibers in control animals and high levels of SUMOylated proteins were present in all fibers during CMV. Finally, previously reported VIDD biomarkers and therapeutic targets were also identified in our datasets which may play an important role in response to muscle weakness seen in ICU patients.

Project description:BackgroundMechanical 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.ObjectiveThese 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.DesignCause 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).InterventionsNone.Measurements and main resultsCompared 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.ConclusionsThese 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.

Project description:Previous workers have demonstrated that controlled mechanical ventilation results in diaphragm inactivity and elicits a rapid development of diaphragm weakness as a result of both contractile dysfunction and fiber atrophy. Limited data exist regarding the impact of pressure support ventilation, a commonly used mode of mechanical ventilation-that permits partial mechanical activity of the diaphragm-on diaphragm structure and function. We carried out the present study to test the hypothesis that high-level pressure support ventilation decreases the diaphragm pathology associated with CMV.Sprague-Dawley rats were randomly assigned to one of the following five groups:1) control (no mechanical ventilation); 2) 12 hrs of controlled mechanical ventilation (12CMV); 3) 18 hrs of controlled mechanical ventilation (18CMV); 4) 12 hrs of pressure support ventilation (12PSV); or 5) 18 hrs of pressure support ventilation (18PSV).We carried out the following measurements on diaphragm specimens: 4-hydroxynonenal-a marker of oxidative stress, active caspase-3 (casp-3), active calpain-1 (calp-1), fiber type cross-sectional area, and specific force (sp F). Compared with the control, both 12PSV and 18PSV promoted a significant decrement in diaphragmatic specific force production, but to a lesser degree than 12CMV and 18CMV. Furthermore, 12CMV, 18PSV, and 18CMV resulted in significant atrophy in all diaphragm fiber types as well as significant increases in a biomarker of oxidative stress (4-hydroxynonenal) and increased proteolytic activity (20S proteasome, calpain-1, and caspase-3). Furthermore, although no inspiratory effort occurs during controlled mechanical ventilation, it was observed that pressure support ventilation resulted in large decrement, approximately 96%, in inspiratory effort compared with spontaneously breathing animals.High levels of prolonged pressure support ventilation promote diaphragmatic atrophy and contractile dysfunction. Furthermore, similar to controlled mechanical ventilation, pressure support ventilation-induced diaphragmatic atrophy and weakness are associated with both diaphragmatic oxidative stress and protease activation.

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Mechanical ventilation reduces rat diaphragm blood flow and impairs oxygen delivery and uptake.

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Mechanical ventilation reduces rat diaphragm blood flow and impairs oxygen delivery and uptake.

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