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Effects of glycemic control on glucose utilization and mitochondrial respiration during resuscitated murine septic shock.

ABSTRACT: BACKGROUND:This study aims to test the hypothesis whether lowering glycemia improves mitochondrial function and thereby attenuates apoptotic cell death during resuscitated murine septic shock. METHODS:Immediately and 6 h after cecal ligation and puncture (CLP), mice randomly received either vehicle or the anti-diabetic drug EMD008 (100 ?g?·?g(-1)). At 15 h post CLP, mice were anesthetized, mechanically ventilated, instrumented and rendered normo- or hyperglycemic (target glycemia 100?±?20 and 180?±?50 mg?·?dL(-1), respectively) by infusing stable, non-radioactive isotope-labeled (13)C6-glucose. Target hemodynamics was achieved by colloid fluid resuscitation and continuous i.v. noradrenaline, and mechanical ventilation was titrated according to blood gases and pulmonary compliance measurements. Gluconeogenesis and glucose oxidation were derived from blood and expiratory glucose and (13)CO2 isotope enrichments, respectively; mathematical modeling allowed analyzing isotope data for glucose uptake as a function of glycemia. Postmortem liver tissue was analyzed for HO-1, AMPK, caspase-3, and Bax (western blotting) expression as well as for mitochondrial respiratory activity (high-resolution respirometry). RESULTS:Hyperglycemia lowered mitochondrial respiratory capacity; EMD008 treatment was associated with increased mitochondrial respiration. Hyperglycemia decreased AMPK phosphorylation, and EMD008 attenuated both this effect as well as the expression of activated caspase-3 and Bax. During hyperglycemia EMD008 increased HO-1 expression. During hyperglycemia, maximal mitochondrial oxidative phosphorylation rate was directly related to HO-1 expression, while it was unrelated to AMPK activation. According to the mathematical modeling, EMD008 increased the slope of glucose uptake plotted as a function of glycemia. CONCLUSIONS:During resuscitated, polymicrobial, murine septic shock, glycemic control either by reducing glucose infusion rates or EMD008 improved glucose uptake and thereby liver tissue mitochondrial respiratory activity. EMD008 effects were more pronounced during hyperglycemia and coincided with attenuated markers of apoptosis. The effects of glucose control were at least in part due to the up-regulation of HO-1 and activation of AMPK.

SUBMITTER: Vogt JA

PROVIDER: S-EPMC4678133 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Effects of glycemic control on glucose utilization and mitochondrial respiration during resuscitated murine septic shock.

Vogt Josef A JA Wachter Ulrich U Wagner Katja K Calzia Enrico E Gröger Michael M Weber Sandra S Stahl Bettina B Georgieff Michael M Asfar Pierre P Fontaine Eric E Radermacher Peter P Leverve Xavier M XM Wagner Florian F

Intensive care medicine experimental 20140603 1

<h4>Background</h4>This study aims to test the hypothesis whether lowering glycemia improves mitochondrial function and thereby attenuates apoptotic cell death during resuscitated murine septic shock.<h4>Methods</h4>Immediately and 6 h after cecal ligation and puncture (CLP), mice randomly received either vehicle or the anti-diabetic drug EMD008 (100 μg · g(-1)). At 15 h post CLP, mice were anesthetized, mechanically ventilated, instrumented and rendered normo- or hyperglycemic (target glycemia ...[more]

PMID: 26266919

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Project description:IntroductionIncreasing evidence supports a role for mitochondrial dysfunction in organ injury and immune dysregulation in sepsis. Although differential expression of mitochondrial genes in blood cells has been reported for several diseases in which bioenergetic failure is a postulated mechanism, there are no data about the blood cell mitochondrial transcriptome in pediatric sepsis.MethodsWe conducted a focused analysis using a multicenter genome-wide expression database of 180 children ≤ 10 years of age with septic shock and 53 healthy controls. Using total RNA isolated from whole blood within 24 hours of PICU admission for septic shock, we evaluated 296 nuclear-encoded mitochondrial genes using a false discovery rate of 1%. A series of bioinformatic approaches were applied to compare differentially expressed genes across previously validated gene expression-based subclasses (groups A, B, and C) of pediatric septic shock.ResultsIn total, 118 genes were differentially regulated in subjects with septic shock compared to healthy controls, including 48 genes that were upregulated and 70 that were downregulated. The top scoring canonical pathway was oxidative phosphorylation, with general downregulation of the 51 genes corresponding to the electron transport system (ETS). The top two gene networks were composed primarily of mitochondrial ribosomal proteins highly connected to ETS complex I, and genes encoding for ETS complexes I, II, and IV that were highly connected to the peroxisome proliferator activated receptor (PPAR) family. There were 162 mitochondrial genes differentially regulated between groups A, B, and C. Group A, which had the highest maximum number of organ failures and mortality, exhibited a greater downregulation of mitochondrial genes compared to groups B and C.ConclusionsBased on a focused analysis of a pediatric septic shock transcriptomic database, nuclear-encoded mitochondrial genes were differentially regulated early in pediatric septic shock compared to healthy controls, as well as across genotypic and phenotypic distinct pediatric septic shock subclasses. The nuclear genome may be an important mechanism contributing to alterations in mitochondrial bioenergetic function and outcomes in pediatric sepsis.

Project description:Downregulation of the hydrogen sulfide (H2S)-producing enzymes cystathionine-?-lyase (CSE), cystathionine-?-synthase (CBS), and/or 3-mercaptopyruvate sulfurtransferase (3-MST) is associated with chronic cardiovascular pathologies. Nevertheless, equivocal data are available on both the expression and function of these enzymes in coronary arteries (CA). We recently reported that atherosclerotic pigs subjected to sepsis developed impaired cardiac function, which coincided with decreased myocardial CSE expression and increased nitrotyrosine formation. To define the endogenous source(s) of H2S in the CA, we studied the expression of CBS, CSE, or 3-MST in the CA of pigs subjected to septic shock with/without pre-existing cardiovascular co-morbidity.Anesthetized and instrumented FBM "familial hypercholesterolemia Bretoncelles Meishan" pigs with high-fat diet-induced hypercholesterolemia and atherosclerosis were subjected to polymicrobial septic shock, or sham procedure, and subsequent intensive care therapy for 24 h. Young German domestic pigs were used as naïve controls. CSE, CBS, 3-MST, HO-1, eNOS, and nitrotyrosine expression was quantified by immunohistochemistry of formalin-fixed paraffin sections.FBM pigs, in the absence of septic shock, showed decreased CSE expression in the media. This decrease became more pronounced after sepsis. The expression pattern of HO-1 resembled the pattern of CSE expression. CBS protein was not detected in the media of any of the CA examined but was localized to the adventitia and only in the atheromatous plaques containing foam cells of the CA, in regions that also displayed abundant nitrotyrosine formation. The CBS expression in the adventitia was not associated with nitrotyrosine formation. 3-MST expression was not found in any of the CA samples.We hypothesize that (i) the reduced CSE expression in FBM pigs may contribute to their cardiovascular disease phenotype and moreover (ii) the further decrease in CA CSE expression in sepsis may contribute to the sepsis-associated cardiac dysfunction.

Project description:BackgroundReduced cellular ATP synthesis due to impaired mitochondrial function of immune cells may be a factor influencing the immune response in septic shock. We investigate changes in mitochondrial function and bioenergetics of human monocytes and lymphocyte subsets.MethodsThirty patients with septic shock were studied at ICU admission, after 24 and 48 hours, and after resolution of shock. Enzymatic activities of citrate synthase and mitochondrial complexes I, IV, and ATP synthase and ATP content of monocytes, T-cells and B-cells and pro-inflammatory (IL-1β and IL-6) and anti-inflammatory (IL-10) cytokine plasma concentrations were compared to samples from 20 healthy volunteers.ResultsLarge variations in mitochondrial enzymatic activities of immune cells of septic patients were detected. In monocytes, maximum levels of citrate synthase activity in sepsis were significantly lower when compared to controls (p = 0.021). Maximum relative enzymatic activity (ratio relative to citrate synthase activity) of complex I (p<0.001), complex IV (p = 0.017) and ATP synthase (p<0.001) were significantly higher. In T-cells, maximum levels of citrate synthase (p = 0.583) and relative complex IV (p = 0.602) activity did not differ between patients and controls, whereas levels of relative complex I (p = 0.006) and ATP synthase (p = 0.032) were significantly higher in septic patients. In B-cells of patients, maximum levels of citrate synthase activity (p = 0.004) and relative complex I (p<0.001) were significantly higher, and mean levels of relative complex IV (p = 0.042) lower than the control values, whereas relative ATP synthase activity did not differ (p = 1.0). No significant difference in cellular ATP content was detected in any cell line (p = 0.142-0.519). No significant correlations between specific cytokines and parameters of mitochondrial enzymatic activities or ATP content were observed.ConclusionsSignificant changes of mitochondrial enzymatic activities occur in human peripheral blood immune cells in septic shock when compared to healthy controls. Assessed sub-types of immune cells showed differing patterns of regulation. Total ATP-content of human immune cells did not differ between patients in septic shock and healthy volunteers.

Project description:ObjectivesIn 2001, a randomized trial showed decreased mortality with early, goal-directed therapy in septic shock, a strategy later recommended by the Surviving Sepsis Campaign. Placement of a central venous catheter is necessary to administer goal-directed therapy. We sought to evaluate nationwide trends in: 1) central venous catheter utilization and 2) the association between early central venous catheter insertion and mortality in patients with septic shock.DesignWe retrospectively analyzed the proportion of septic shock cases receiving an early (day of admission) central venous catheter and the odds of hospital mortality associated with receiving early central venous catheter from years 1998 to 2001 compared with 2002 to 2009.SettingNon-federal acute care hospitalizations from the Nationwide Inpatient Sample, 1998-2009.PatientsA total of 203,481 (population estimate: 999,545) patients admitted through an emergency department with principal diagnosis of septicemia and secondary diagnosis of shock.InterventionsNone.Measurements and main resultsFrom 1998 to 2009, population-adjusted rates of septic shock increased from 12.6 cases per 100,000 U.S. adults to 78 cases per 100,000. During this time, age-adjusted hospital mortality associated with septic shock declined from 40.4% to 31.4%. Early central venous catheter insertion increased from 5.7% (95% confidence interval 5.1% to 6.3%) to 19.2% (95% confidence interval 18.7% to 19.5%) cases with septic shock, with an increased rate of early central venous catheter placement identified after 2007. The rate of decline in age-adjusted hospital mortality was significantly greater for patients who received an early central venous catheter (-4.2% per year, 95% confidence interval -3.2, -4.2%) as compared with no central venous catheter (-2.9% per year, 95% confidence interval -2.3, -3.5%; p = 0.016). Hospital mortality associated with early central venous catheter insertion significantly decreased from a multivariable-adjusted odds ratio of 1.29 (95% confidence interval 1.14-1.45) prior to 2001 to an adjusted odds ratio of 0.87 (95% confidence interval 0.84-0.90) after 2001.ConclusionsPlacement of a central venous catheter early in septic shock has increased three-fold since 1998. The mortality associated with early central venous catheter insertion decreased after publication of evidence-based instructions for central venous catheter use.

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Effects of glycemic control on glucose utilization and mitochondrial respiration during resuscitated murine septic shock.

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Effects of glycemic control on glucose utilization and mitochondrial respiration during resuscitated murine septic shock.

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