C019 Protéine C activ ée et glucocorticoïdes sont synergiques dans le choc septique expérimental

IntroductionLa Protéine C Activée (PCa) et les glucocorticoïdes sont recommandés dans le traitement du choc septique. Le but de notre étude est de comparer dans deux modèles de choc expérimentaux les effets de la dexaméthasone (glucocorticoïde de référence chez le rat) (Dexa) et de la PCa, seuls ou en association.Matériels et MéthodesDeux modèles de choc chez le rat Wistar : LPS sédaté (10mg/kg) ou CLP chroniquement perfusé + antibiothérapie plus expansion volémique continue (10ml/kg/h) 4 heures après la chirurgie.Traitements et groupes : Sham LPS ou CLP, Dexa [(1mg/kg IV bolus (LPS) ou 2mg/kg/24h IV continue (CLP)], PCa : Xigris, 33 μg/kg/h, PCa + D exa (PCaD)Mesures : PAM, Fc, débit aortique, laser-doppler et PO2 musculaire, lactates, vasoréactivité à la noradrénaline, TNF, NOx et prélèvements tissulaires pour études des voies de signalisation (MAPk, ERK1/2, iNOS, eNOS, glucocorticoïde receptor, ..).Résultats+/- = p<0.05vs LPS/CLP ++/-- = p<0.05vs autres groupesDans le groupe LPS, le débit et la PO2 musculaire sont améliorés par PCa+Dexa. La vasoréactivité diminuée par le sepsis est améliorée par tous les traitements sans différence entre les groupes.ConclusionDans les deux modèles, la combinaison PCa+Dexa est associé à une amélioration marquée des paramètres hémodynamiques et de perfusion tissulaire, une baisse importante des lactates ainsi qu’une amélioration de la survie. L’étude des voies de signalisation à venir devrait nous permettre de mieux préciser les mécanismes en cause

Vascular hyporesponsiveness to vasopressors in septic shock: from bench to bedside

PurposeTo delineate some of the characteristics of septic vascular hypotension, to assess the most commonly cited and reported underlying mechanisms of vascular hyporesponsiveness to vasoconstrictors in sepsis, and to briefly outline current therapeutic strategies and possible future approaches. Methods Source data were obtained from a PubMed search of the medical literature with the following MeSH terms: Muscle, smooth, vascular/physiopathology; hypotension/etiology; shock/physiopathology; vasodilation/physiology; shock/therapy; vasoconstrictor agents. Results Nitric oxide (NO) and peroxynitrite are crucial components implicated in vasoplegia and vascular hyporeactivity. Vascular ATP-sensitive and calcium-activated potassium channels are activated during shock and participate in hypotension. In addition, shock state is characterized by inappropriately low plasma glucocorticoid and vasopressin concentrations, a dysfunction and desensitization of alpha-receptors, and an inactivation of catecholamines by oxidation. Numerous other mechanisms have been individualized in animal models, the great majority of which involve NO: MEK1/2–ERK1/2 pathway, H2S, hyperglycemia, and cytoskeleton dysregulation associated with decreased actin expression. Conclusions Many therapeutic approaches have proven their efficiency in animal models, especially therapies directed against one particular compound, but have otherwise failed when used in human shock. Nevertheless, high doses of catecholamines, vasopressin and terlipressin, hydrocortisone, activated protein C, and non-specific shock treatment have demonstrated a partial efficiency in reversing sepsis-induced hypotension

Recombinant human activated protein C improves endotoxemia-induced endothelial dysfunction: a blood-free model in isolated mouse arteries

Recombinant human activated protein C (rhAPC) is one of the treatment panels for improving vascular dysfunction in septic patients. In a previous study, we reported that rhAPC treatment in rat endotoxemia improved vascular reactivity, although the mechanisms involved are still under debate. In the present study, we hypothesized that rhAPC may improve arterial dysfunction through its nonanticoagulant properties. Ten hours after injection of LPS in mice (50 mg/kg ip), aortic rings and mesenteric arteries were isolated and incubated with or without rhAPC for 12 h. Aortic rings were mounted in a myograph, after which arterial contractility and endothelium-dependent relaxation were measured in the presence or absence of nitric oxide synthase or cyclooxygenase inhibitors. Flow (shear stress)-mediated dilation with or without the above inhibitors was also measured in mesenteric resistance arteries. Protein expression was assessed by Western blotting. Lipopolysaccharide (LPS) reduced aortic contractility to KCl and phenylephrine as well as dilation to acetylcholine. LPS also reduced flow-mediated dilation in mesenteric arteries. In rhAPC-treated aorta and mesenteric arteries, contractility and endothelial responsiveness to vasodilator drug and shear stress were improved. rhAPC treatment also improved LPS-induced endothelial dysfunction; this effect was associated with an increase in the phosphorylated form of endothelial nitric oxide synthase and protein kinase B as well as cyclooxygenase vasodilatory pathways, thus suggesting that these pathways, together with the decrease in nuclear factor-κB activation and inducible nitric oxide synthase expression in the vascular wall, are implicated in the endothelial effect of rhAPC. In conclusion, ex vivo application of rhAPC improves arterial contractility and endothelial dysfunction resulting from endotoxemia in mice. This finding provides important insights into the mechanism underlying rhAPC-induced improvements on arterial dysfunction during septic shock

Activated protein C improves LPS-induced cardiovascular dysfunction by decreasing tissular inflammation and oxidative stress.

BACKGROUND:: Recombinant human activated Protein C (APC) is used as an adjunctive therapeutic treatment in septic shock. APC seemingly acts on coagulation-inflammation interaction but also by decreasing proinflammatory gene activity, thus inhibiting subsequent production of proinflammatory cytokines, NO and NO-induced mediators, reactive oxygen species production and leukocyte-endothelium interaction. The hemodynamic effects of APC on arterial pressure and cardiac function are now well established in animal models. However, the specific effects of APC on heart and vessels have never been studied. OBJECTIVES:: To investigate the potential protective properties of therapeutic ranges of APC on a rat endotoxic shock model in terms of anti-inflammatory and cytoprotective pathways. DESIGN:: Laboratory investigation. SETTING:: University medical center research laboratory. INTERVENTIONS:: Rats were exposed to lipopolysaccharide (LPS) (10 mg/Kg iv.). Endotoxic shock was treated with infusion of saline with or without APC (33 mug/kg/h) during 4 hrs. Hemodynamic parameters were continuously assessed and measurements of muscle oxygen partial pressures, NO and superoxide anion (O2) by spin trapping, of NF-kappaB, metalloproteinase-9 (MMP-9) and inducible NO synthase (iNOS) by Western blotting, as well as leukocyte infiltration and MMP-9 activity were performed at both the heart and aorta level (tissue). MAIN RESULTS:: APC partially prevented the reduction of blood pressure induced by LPS and improved both vascular hyporeactivity and myocardial performance. This was associated with a decreased up-regulation of NF-kappaB, iNOS and MMP-9. LPS-induced tissue increases in NO and O2 production were decreased by APC. Furthermore, APC decreased tissue leukocyte infiltration/activation as assessed by a decrease in myeloperoxydase and matrix metalloproteinase 9 activity. CONCLUSIONS:: These data suggest that APC improves cardiovascular function i) by modulating the endotoxin induced-proinflammatory/prooxydant state, ii) by decreasing endothelial/leukocyte interaction and iii) by favoring stabilization of the extracellular matrix