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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Glycogen synthase kinase 3beta (GSK-3beta) is a serine/threonine protein kinase that has recently emerged as a key regulatory switch in the modulation of the inflammatory response. Dysregulation of GSK-3beta has been implicated in the pathogenesis of several diseases including sepsis. Here we investigate the effects of 2 chemically distinct inhibitors of GSK-3beta, TDZD-8 and SB216763, on the circulatory failure and the organ injury and dysfunction associated with hemorrhagic shock. ⋯ In addition, TDZD-8, but not SB216763, attenuated the increase caused by hemorrhage and resuscitation in plasma levels of the proinflammatory cytokine interleukin 6 and also of the anti-inflammatory cytokine interleukin 10. Neither of the GSK-3beta inhibitors however affected the delayed fall in blood pressure caused by hemorrhagic shock. Thus, we propose that inhibition of GSK-3beta may represent a novel therapeutic approach in the therapy of hemorrhagic shock.
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Both fluid management and renal replacement therapies play a fundamental role in the treatment of critically ill patients. In a recent in vitro study, we have shown specific interactions of different colloids and the hemocompatibility of hemofilters. The present study was performed to compare the five most common fluids for volume resuscitation, i.e., normal saline (SAL), hydroxyethyl starch 130 kd/0.4 (HES130), hydroxyethyl starch 200 kd/0.5 (HES200), albumin (ALB), and gelatin (GEL) with respect to their interaction with continuous venovenous hemofiltration (CVVH) in anesthetized domestic pigs. ⋯ Direct in vivo effects of colloids in anaesthetized and ventilated pigs are not predictable for their effects during CVVH. Interaction between CVVH and every volume substitute occur in a highly specific manner. This observation could be helpful to explain contradictory study results and should be considered for future study designs.
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Excessive NO has been shown to play a major role in the pathogenesis of multiple organ dysfunctions in septic condition. Burn injury, especially if it is associated with smoke inhalation, is often complicated by subsequent development of pneumonia or sepsis that determine the outcome. In the present study, we developed an ovine sepsis model, created by exposing sheep to smoke inhalation followed by instillation of bacteria into the airway, that closely mimics human sepsis and pneumonia. ⋯ The hypotension seen in nontreated animals was not ameliorated either. The increase in plasma concentration of nitrate and nitrite was inhibited by BBS-2. The results of present study show that iNOS may be partially involved in the pathogenesis of acute lung injury induced by smoke inhalation followed by bacterial instillation in the airway.
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We have reported that toxic factors in intestinal lymph are responsible for acute lung injury and bone marrow suppression and that they contribute to a systemic inflammatory state based on studies in rodent models of trauma-hemorrhagic shock. Rodent models may not completely reflect the responses of injured patients. Thus, it is important to confirm these findings in primates before applying them to injured human patients with trauma. ⋯ The results of these studies indicate that PMN treated with baboon T/HS lymph showed significantly induced respiratory burst responses compared with PMN treated with T/SS lymph or medium when phorbol myristate acetate PMA was applied after lymph pretreatment. Secondly, we found that the expression of CD11b adhesion molecule was increased by incubation with T/HS lymph. These results suggest that baboon lymph from T/HS models can increase respiratory burst and adhesion molecule expression in human PMN, thereby potentially contributing to PMN-mediated organ injury.
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This study was performed to determine whether endotoxemia causes diastolic cardiac dysfunction. Eleven healthy volunteers, 30 +/- 6 years of age, underwent comprehensive transthoracic echocardiographic assessment including two-dimensional, M-mode transmitral and tissue Doppler of systolic and diastolic function at baseline and at 3 and 5 h after intravenous administration of purified Escherichia coli endotoxin (4 ng/kg). Data were analyzed by analysis of variance; P values of less than 0.05 were considered significant. ⋯ The observed decreases in E/A (transmitral) and E/A (tissue Doppler) ratio were primarily due to increases in A and A. Moreover, isovolumic relaxation time and time constant for left ventricular relaxation, a load-independent parameter for ventricular relaxation, remained unchanged at 3 and 5 h after endotoxin infusion. Therefore, our findings are more likely due to enhanced atrial contractility resulting from increased sympathetic activity in response to reduction in left ventricular afterload and not due to altered diastolic filling characteristics.