Shock : molecular, cellular, and systemic pathobiological aspects and therapeutic approaches : the official journal the Shock Society, the European Shock Society, the Brazilian Shock Society, the International Federation of Shock Societies
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The present study was designed to investigate the proteomic alteration of hepatic mitochondria during sepsis and to explore the possible effects induced by heat shock treatment. Sepsis was induced by cecal ligation and puncture in Sprague-Dawley rats. Liver mitochondrial proteins were isolated and evaluated by 2-dimensional electrophoresis with broad pH-ranged (pH 3 - 10) immobile DryStrip and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. ⋯ Phosphoprotein staining showed that the degree of phosphorylation is higher in MP1 and MP2 than that in MP3. The enzyme activity assay showed that ALDH2 activity was downregulated in nonheated septic rats of 18 h after cecal ligation and puncture operation, and preserved in heated septic rats. The results of this study suggest that posttranslation modification, highly possible the phosphorylation, in ALDH2 may play a functional role in the pathogenesis of sepsis and provide a novel protective mechanism of heat shock treatment.
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Peptide kinins are potent vasoactive agents in the microcirculation that might be released after burn injury. The present study was designed to test the hypothesis that Icatibant (JE 049), a potent, selective peptidomimetic bradykinin-B2 receptor antagonist, would reduce the cardiovascular pathology occurring in sheep exposed to 40% total body surface area (TBSA), third-degree burn. Female sheep were surgically prepared for chronic study. ⋯ Both low and high doses of Icatibant significantly reduced the microvascular fluid flux: Icatibant-4 (0 h, 5.3 +/- 0.6; 24 h, 17.5 +/- 3.5; 48 h, 20.3 +/- 3.4); Icatibant-20 (0 h, 5.3 +/- 1.1; 24 h, 15.2 +/- 2; 48 h, 17.6 +/- 4.1). Total prefemoral protein leak was reduced in all treatment groups. The low dose of Icatibant significantly reduced prefemoral lymph flow without adversely affecting the hemodynamic changes observed after burn injury in sheep, suggesting that the bradykinin antagonist would reduce edema formation and improve fluid management of thermally injured patients.
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Randomized Controlled Trial
Glibenclamide dose response in patients with septic shock: effects on norepinephrine requirements, cardiopulmonary performance, and global oxygen transport.
Adenosine triphosphate-sensitive potassium channels are important regulators of arterial vascular smooth muscle tone and are implicated in the pathophysiology of catecholamine tachyphylaxis in septic shock. The present study was designed as a prospective, randomized, double-blinded, clinical pilot study to determine whether different doses of glibenclamide have any effects on norepinephrine requirements, cardiopulmonary hemodynamics, and global oxygen transport in patients with septic shock. We enrolled 30 patients with septic shock requiring invasive hemodynamic monitoring and norepinephrine infusion of 0.5 microg.kg-1.min-1 or greater to maintain MAP between 65 and 75 mmHg. ⋯ Glibenclamide decreased plasma glucose concentrations in a dose-dependent manner but failed to reduce norepinephrine requirements. None of the doses had any effects on cardiopulmonary hemodynamics, global oxygen transport, gas exchange, or electrolytes. These data suggest that oral glibenclamide in doses from 10 to 30 mg fails to counteract arterial hypotension and thus to reduce norepinephrine requirements in catecholamine-dependent human septic shock.
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Microcirculatory dysfunction contributes significantly to tissue hypoxia and multiple organ failure in sepsis. Ischemia of the gut and intestinal hypoxia are especially relevant for the evolution of sepsis because the mucosal barrier function may be impaired, leading to translocation of bacteria and toxins. Because sympathetic blockade enhances intestinal perfusion under physiologic conditions, we hypothesized that thoracic epidural anesthesia (TEA) may attenuate microcirculatory perturbations during sepsis. ⋯ Notably, TEA did not impair systemic hemodynamic variables beyond the changes caused by sepsis itself. Therefore, sympathetic blockade may represent a therapeutic option to treat impaired microcirculation in the gut mucosa resulting from sepsis. Additional studies are warranted to assess the microcirculatory effects of sympathetic blockade on other splanchnic organs in systemic inflammation.
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Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a nuclear receptor that regulates diverse biological functions including inflammation. The PPARgamma ligands have been reported to exert cardioprotective effects and attenuate myocardial reperfusion injury. Here, we examined the molecular mechanisms of their anti-inflammatory effects. ⋯ The cardioprotection afforded by ciglitazone was attenuated by the PPAR-gamma antagonist GW-9662. In contrast, GW-9662 did not affect the beneficial effects afforded by 15d-PGJ2. Thus, our data suggest that treatment with these chemically unrelated PPAR-gamma ligands results in diverse anti-inflammatory mechanisms.