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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Blunt chest trauma impairs the outcome of multiply-injured patients. Lung contusion induces inflammatory alterations and Fas-dependent apoptosis of alveolar type 2 epithelial (AT2) cells has been described. The Fas/Fas ligand (FasL) system seems to exhibit a proinflammatory potential. ⋯ The proinflammatory response of AMΦs is enhanced by FasL stimulation. Both AMΦs and AT2 cells seem to contribute to the mediator release after lung contusion. These results confirm the importance of the Fas/FasL system in the inflammatory response after chest trauma.
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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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Blunt chest trauma resulting in pulmonary contusion is a common but poorly understood injury. We previously demonstrated that lung contusion activates localized and systemic innate immune mechanisms and recruits neutrophils to the injured lung. We hypothesized that the innate immune and inflammatory activation of neutrophils may figure prominently in the response to lung injury. ⋯ We show that CXCL1, CXCL2/3, and CXCR2 are involved in neutrophil recruitment to the lung after injury and that intercellular adhesion molecule 1 is locally expressed and actively participates in this process. Injured gp91-deficient mice showed improved lung function, indicating that oxidant production by neutrophil NADPH oxidase mediates lung dysfunction after contusion. These data suggest that both neutrophil presence and function are required for lung injury after lung contusion.