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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Sepsis-induced microvascular leukocyte/endothelial cell interaction may result in a deterioration of capillary perfusion that finally leads to septic organ dysfunction. The aim of the present study was to characterize a novel, sublethal, two-hit model of chronic systemic sepsis that allows the repeated analysis of microcirculation by intravital microscopy. In Syrian golden hamsters the effect of a single i.v. endotoxin (LPS, 2 mg/kg, E. coli) injection (SH-LPS group, n = 5 animals) vs. a double LPS injection (DH-LPS group, n = 6 animals) was analyzed. ⋯ SH-LPS: 3.0 +/- 13%; P < 0.05). In parallel, coagulatory parameters were found significantly altered only in DH-LPS animals but not in SH-LPS animals. We conclude that "double hit" LPS exposure is an appropriate model (i) to analyze repeatedly over time microcirculatory disorders under conditions of persistent endotoxemia-induced inflammatory response, and (ii) to prove the effectiveness of novel anti-inflammatory strategies.
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Using a zymosan-induced mouse model of multiple organ dysfunction syndrome (MODS), it has been shown that the absence of MIP-1alpha increased mortality fourfold, whereas the absence of C5 decreased mortality fourfold. The purpose of the present study was to determine the early events following zymosan injection in MIP-1alpha knockout and C5-deficient mice. B10. ⋯ The presence or absence of either C5 or MIP-1alpha did not affect early pulmonary neutrophil sequestration. Organ histopathology suggested early neutrophil infiltration in the lung and spleen within 48 h. These studies indicate that MIP-1alpha and C5 play a critical role in modulating cellular changes associated with lethality in a zymosan model of MODS.
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Reactive oxygen species (ROS) contribute to the multiple organ failure (MOF) in hemorrhagic shock. Here we investigate the effects of a membrane-permeable radical scavenger (tempol) on the circulatory failure and the organ injury and dysfunction (kidney, liver, lung, intestine) associated with hemorrhagic shock in the anesthetized rat. ⋯ Treatment of rats upon resuscitation with the membrane-permeable radical scavenger tempol (30 mg/kg bolus injection followed by an infusion of 30 mg/kg/h i.v.) attenuated the delayed circulatory failure as well as the multiple organ injury and dysfunction associated with hemorrhagic shock. Thus, we propose that an enhanced formation of ROS and/or peroxynitrite importantly contributes to the MOF in hemorrhagic shock, and that membrane-permeable radical scavengers, such as tempol, may represent a novel therapeutic approach for the therapy of hemorrhagic shock.
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Persistent vasodilation refractory to vasopressor agents is characteristic of septic shock. Induction of nitric oxide synthase (NOS) by sepsis-induced cytokines within the vasculature is one of the primary mediators of this refractory vasodilation. To evaluate the mechanism of vasodilation in sepsis, we used in vivo videomicroscopy to measure microvascular vasoconstrictive responses to topical suffusion of norepinephrine in mice made septic by cecal ligation and puncture, and contrasted the effects of topical superfusion of the nonselective NOS inhibitor N(G)-methyl-L-arginine (L-NMMA) and the selective inducible NOS (iNOS) inhibitor S-methyl-isothiourea (SMT). ⋯ When excess (1 mM) L-arginine, the substrate for NOS, was added to the superfusion buffer along with both SMT and L-NMMA, arteriolar responsiveness to norepinephrine was decreased to the original values. These experiments demonstrate that iNOS inhibition is as effective as nonselective NOS inhibition in reversing decreased catecholamine reactivity in sepsis. This suggests a crucial role for microvascular activation of iNOS in the pathophysiology of hypotension and decreased vasopressor responsiveness in sepsis.
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Adequate resuscitation of patients from shock states depends on restoration of oxygen delivery (DO2) to tissues. Direct measurement of systemic DO2 during shock states requires invasive techniques such as pulmonary artery catheterization. These experiments were performed to examine the ability of near-infrared spectroscopy (NIRS), to measure regional tissue oxygenation in a large-animal model of hemorrhagic shock, and to compare these measures to global measures of oxygen delivery. ⋯ Intramucosal pH did not correlate well with DO2. Regional tissue oxygenation as measured by NIRS shows excellent correlation with global oxygen delivery. NIRS may allow estimation of systemic oxygen delivery using rapid non-invasive techniques.