Comparative effects of recombinant human activated protein C and dexamethasone in experimental septic shock

Bouazza, Youcef; Sennoun, N.; Strub, Charlène; Régnault, V.; Gibot, Sébastien; Meziani, Ferhat; Lacolley, Patrick; Lévy, Bruno

doi:10.1007/s00134-011-2327-9

Cited by 11 publications

(4 citation statements)

References 35 publications

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“…GC-GRα is also strongly involved in vascular development (81). Experimental studies have shown GR-dependent upregulation of multiple mediators involved in endothelial cell homeostasis, such as sphingosine kinase 1 (SphK1) (157), angiopoietin-1 (Angpt-1) (158), serum glucocorticoid kinase-1 (SGK-1) (159,160), GILZ (161), and eNOS (162)(163)(164). In experimental ARDS, upregulation of SphK1, an important regulator of endothelial barrier integrity, was shown to improve alveolo-capillary membrane (ACM) permeability (157).…”

Section: Endotheliummentioning

confidence: 99%

“…In murine sepsis, GC treatment attenuated renal dysfunction by reducing mitochondrial injury with preservation of cytochrome c oxidase and suppression of pro-apoptotic protein levels (232). In clinical (233,234) and experimental (162,235) randomized trials, participants with severe sepsis receiving GC treatment had, in comparison to controls, a significant reduction in (i) circulating nitric oxide levels (162,233,235), and (ii) spontaneous release of hydrogen peroxide (H 2 O 2 ) by neutrophils (234).…”

Section: Oxidative Stress and Circimentioning

confidence: 99%

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General Adaptation in Critical Illness: Glucocorticoid Receptor-alpha Master Regulator of Homeostatic Corrections

Meduri

Chrousos

2020

Front. Endocrinol.

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In critical illness, homeostatic corrections representing the culmination of hundreds of millions of years of evolution, are modulated by the activated glucocorticoid receptor alpha (GRα) and are associated with an enormous bioenergetic and metabolic cost. Appreciation of how homeostatic corrections work and how they evolved provides a conceptual framework to understand the complex pathobiology of critical illness. Emerging literature place the activated GRα at the center of all phases of disease development and resolution, including activation and re-enforcement of innate immunity, downregulation of pro-inflammatory transcription factors, and restoration of anatomy and function. By the time critically ill patients necessitate vital organ support for survival, they have reached near exhaustion or exhaustion of neuroendocrine homeostatic compensation, cell bio-energetic and adaptation functions, and reserves of vital micronutrients. We review how critical illness-related corticosteroid insufficiency, mitochondrial dysfunction/damage, and hypovitaminosis collectively interact to accelerate an anti-homeostatic active process of natural selection. Importantly, the allostatic overload imposed by these homeostatic corrections impacts negatively on both acute and long-term morbidity and mortality. Since the bioenergetic and metabolic reserves to support homeostatic corrections are time-limited, early interventions should be directed at increasing GRα and mitochondria number and function. Present understanding of the activated GC-GRα's role in immunomodulation and disease resolution should be taken into account when re-evaluating how to administer glucocorticoid treatment and co-interventions to improve cellular responsiveness. The activated GRα interdependence with functional mitochondria and three vitamin reserves (B1, C, and D) provides a rationale for co-interventions that include prolonged glucocorticoid treatment in association with rapid correction of hypovitaminosis.

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Section: Endotheliummentioning

confidence: 99%

Section: Oxidative Stress and Circimentioning

confidence: 99%

General Adaptation in Critical Illness: Glucocorticoid Receptor-alpha Master Regulator of Homeostatic Corrections

Meduri

Chrousos

2020

Front. Endocrinol.

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“…Bouazza et al [127] hypothesised that the combination of APC and steroids would be beneficial compared with their individual use in resuscitated septic shock induced by caecal ligation and puncture. They observed that either APC or dexamethasone improved arterial contractility and endothelial dysfunction resulting from septic shock; however, their combination increased survival, thus recommending the re-evaluation of the combined use of APC and steroids.…”

Section: Experimentalsmentioning

confidence: 99%

Year in review in Intensive Care Medicine 2011: I. Nephrology, epidemiology, nutrition and therapeutics, neurology, ethical and legal issues, experimentals

et al. 2012

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“…The fact that NO and superoxide was assessed in aorta instead of mesenteric arteries constitutes a limitation of the study. Although both vascular beds depend on different regulatory mechanisms, we have previously shown that sepsis induced the same kind of hyporeactivity to Phe in aorta and small mesenteric arteries [ 6 , 41 ]. Finally, septic shock is a systemic syndrome, in which vascular inflammation, oxidative and nitrosative stresses are ubiquitous, as we showed in our previous studies [ 42 – 46 ].…”

Section: Discussionmentioning

confidence: 99%

Docosahexaenoic acid, but not eicosapentaenoic acid, improves septic shock-induced arterial dysfunction in rats

et al. 2017

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IntroductionLong chain n-3 fatty acid supplementation may modulate septic shock-induced host response to pathogen-induced sepsis. The composition of lipid emulsions for parenteral nutrition however remains a real challenge in intensive care, depending on their fatty acid content. Because they have not been assessed yet, we aimed at determining the respective effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) during septic shock-induced vascular dysfunction.MethodsIn a peritonitis-induced septic shock model, rats were infused with EPA, DHA, an EPA/DHA mixture or 5% dextrose (D5) during 22 hours. From H18, rats were resuscitated and monitored during 4 hours. At H22, plasma, aorta and mesenteric resistance arteries were collected to perform ex vivo experiments.ResultsWe have shown that septic rats needed an active resuscitation with fluid challenge and norepinephrine treatment, while SHAM rats did not. In septic rats, norepinephrine requirements were significantly decreased in DHA and EPA/DHA groups (10.6±12.0 and 3.7±8.0 μg/kg/min respectively versus 17.4±19.3 μg/kg/min in D5 group, p<0.05) and DHA infusion significantly improved contractile response to phenylephrine through nitric oxide pathway inhibition. DHA moreover significantly reduced vascular oxidative stress and nitric oxide production, phosphorylated IκB expression and vasodilative prostaglandin production. DHA also significantly decreased polyunsaturated fatty acid pro-inflammatory mediators and significantly increased several anti-inflammatory metabolites.ConclusionsDHA infusion in septic rats improved hemodynamic dysfunction through decreased vascular oxidative stress and inflammation, while EPA infusion did not have beneficial effects.

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Comparative effects of recombinant human activated protein C and dexamethasone in experimental septic shock

Cited by 11 publications

References 35 publications

General Adaptation in Critical Illness: Glucocorticoid Receptor-alpha Master Regulator of Homeostatic Corrections

General Adaptation in Critical Illness: Glucocorticoid Receptor-alpha Master Regulator of Homeostatic Corrections

Year in review in Intensive Care Medicine 2011: I. Nephrology, epidemiology, nutrition and therapeutics, neurology, ethical and legal issues, experimentals

Docosahexaenoic acid, but not eicosapentaenoic acid, improves septic shock-induced arterial dysfunction in rats

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