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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Severe sepsis is frequently associated with microcirculatory abnormalities despite seemingly adequate hemodynamic resuscitation. As increased serum angiotensin II levels may play a role in this dysfunction, we evaluated the microcirculatory effects of enalaprilat in an experimental model of septic shock. One hour after injection of 1.5 g/kg body weight of feces into the abdominal cavity, 16 adult female anesthetized, mechanically ventilated sheep were randomized to receive 2.5 mg enalaprilat or saline. ⋯ There were progressive and significant reductions in the proportion of small perfused vessels and in the microvascular flow index for small vessels (both P < 0.01 for trend) during shock and the first 2 h of norepinephrine infusion in the placebo group, which were prevented by the administration of enalaprilat. There were no differences between treated and placebo groups in global hemodynamic variables, time to shock or median survival time (21.8 [18.6-28.8] vs. 22.9 [21.8-30.0] h; P = 0.45). However, oxygen exchange was worse (PaO2/FiO2 ratio, 224 [128-297] vs. 332 [187-450]; P < 0.05), and creatinine concentrations increased more in the treated group (from 0.51 [0.42-0.75] to 1.19 [0.64-1.50] mg·dL(-1); P = 0.04) than in the control group (from 0.55 [0.45-0.62] to 0.78 [0.46-1.78] mg·dL(-1); P = 0.12), Enalaprilat therefore prevented the worsening of sublingual microcirculatory variables in this fluid-resuscitated, hyperdynamic model of septic shock, without significant effect on arterial pressure, but with a possible deleterious effect on renal and lung function.
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Skeletal muscle damage provokes complex repair mechanisms including recruitment of leukocytes as well as activation of myogenic precursor cells such as satellite cells. To study muscle cell repair mechanisms after muscle fiber damage, we used an in vitro model of scrape-injured myotubes. Exposing vital C2C12 myoblasts and myotubes to cell debris of damaged myotubes revealed mRNA upregulation of adrenomedullin (ADM), insulin-like growth factors 1 and 2, metallopeptidase 9, and monocyte chemoattractant protein11. ⋯ Knockdown of HIF-1α in C2C12 cells proved that activation of HIF-1 in response to cell debris was responsible for upregulating ADM and monocyte chemoattractant protein 1. Furthermore, by incubating cells on gas-permeable culture dishes, we excluded a reduced pericellular pO2 induced by cell debris as the cause for ADM upregulation. Our data suggest that damaged myofibers activate HIF-1 in neighboring myotubes and precursor myoblasts by direct contact, concomitantly upregulating factors necessary for angiogenesis, tissue regeneration, and phagocyte recruitment.
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The reduction of neutrophil migration to an infectious focus is associated with a high mortality in severe sepsis. Previously, we showed that heme oxygenase (HO) products downregulate neutrophil recruitment in a noninfectious inflammatory model. The present study was designed to determine the role of HO in sepsis induced by cecal ligation and puncture (CLP) model. ⋯ Furthermore, hemin resulted in a reduction of neutrophil migration both in vivo and in vitro. Altogether, our results demonstrated that pretreatment with the HO inhibitor prevents the pathological findings in severe CLP. However, the combination of pretreatment plus posttreatment with ZnPP IX enhances sepsis severity because of an increase in circulating levels of heme, which is deleterious to the host tissues and also inhibits neutrophil migration.
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Most experimental studies on hemorrhage and trauma are performed under anesthesia. We determined the effects of three commonly used anesthetic regimens on hemodynamics and organ damage under normal and hemorrhagic/traumatic shock (HTS) conditions in rats. Animals were anesthetized with ketamine/diazepam (K/D), ketamine/xylazine (K/X), or isoflurane (ISO). ⋯ Histological examinations revealed frequent HTS-induced damage to adrenals, kidney, and liver of animals anesthetized with K/D and K/X but not with ISO. Anesthetics differentially affect HTS-induced hemodynamic alterations and organ injury. Thus, when interpreting data from HTS models, the individual effect of anesthetics should be considered.