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 is one of the most important risk factors in acute respiratory distress syndrome (ARDS). beta-Glucan is a potent reticuloendothelial modulating agent, the immunobiological activity of which is mediated in part by an increase in the number and function of macrophages. In this study, we investigated the putative protective role of beta-glucan against sepsis-induced lung injury. Sepsis was induced by cecal ligation and puncture (CLP) in Wistar rats. ⋯ In contrast, beta-1,3-D-glucanase caused a significantly increased MPO and ICAM-1 levels in the lung. These data reveal that beta-glucan treatment improved the course of CLP-induced peritonitis and attenuated the lung injury. Administration of beta-glucanase inhibited the beta-glucan activity and resulted in enhanced lung injury.
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Comparative Study
Mechanisms of direct peritoneal resuscitation-mediated splanchnic hyperperfusion following hemorrhagic shock.
Conventional resuscitation (CR) from hemorrhagic shock causes a persistent and progressive splanchnic vasoconstriction and hypoperfusion despite hemodynamic restoration with intravenous fluid therapy. Adjunctive direct peritoneal resuscitation (DPR) with a clinical peritoneal dialysis solution instilled into the peritoneal cavity has been shown to restore splanchnic tissue perfusion, down-regulate the gut-derived exaggerated systemic inflammatory response, promote early fluid mobilization, and improve overall outcome. This study was conducted to define the molecular mechanisms of DPR-induced gut hyperperfusion after hemorrhagic shock. ⋯ Cyclooxygenase and K(+)Ca2+channels were not active in DPR-mediated microvascular effects. In conclusion, DPR improves splanchnic tissue perfusion by endothelium-dependent mechanisms mediated by activations of glibenclamide-sensitive K(+) channels (KATP), adenosine A1 receptor subtype activation, and nitric oxide release. Direct peritoneal resuscitation preserves endothelial dilatory functions, thereby overriding any endothelium-derived constrictor response triggered by hemorrhagic shock and CR.
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Systemic and microvascular hemodynamic responses to volume restoration from hemorrhagic shock were studied in the hamster window chamber model to determine the significance of blood rheological and oxygen transport properties. Moderated hemorrhage was induced by means of arterial controlled bleeding of 50% of the blood volume. The hypovolemic shock state was maintained for 1 h before resuscitation. ⋯ Oxygen delivery and extraction levels were significantly lower for resuscitation with plasma and MetHb-loaded RBCs compared with oxygen-carrying RBCs. The curtailed recovery of systemic and microvascular conditions after volume restitution with plasma seems to be due to the decrease in blood viscosity. Conversely, the restoration of blood rheological properties improves resuscitation independently of the restitution of oxygen-carrying capacity.
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The cholinergic nervous system controls inflammation by inhibiting the release of proinflammatory cytokines such as tumor necrosis factor (TNF) alpha from lipopolysaccharide (LPS)-stimulated macrophages. The key endogenous mediator of this so-called cholinergic anti-inflammatory pathway is acetylcholine, the principal neurotransmitter of the vagus nerve, which specifically interacts with alpha7 cholinergic receptors expressed by macrophages and other cell types to inhibit TNF-alpha production. We here investigated the capacity of the selective alpha7 cholinergic receptor agonist 3-(2,4-dimethoxybenzylidene) anabaseine (GTS-21) to inhibit LPS-induced inflammatory responses in mice in vivo. ⋯ This inhibitory effect on neutrophil recruitment by GTS-21 was independent of its effect on TNF-alpha release, considering that etanercept, a potent TNF-alpha-blocking protein containing the extracellular domain of the p75 TNF-alpha receptor, did not influence LPS-induced neutrophil influx either in the presence or in the absence of GTS-21 treatment. GTS-21 did not reduce the local secretion of macrophage inflammatory protein 2 and keratinocyte-derived cytokine, suggesting that altered concentrations of these neutrophil-attracting chemokines did not contribute to GTS-21-induced inhibition of neutrophil migration. These data identify a novel anti-inflammatory effect of chemical alpha7 cholinergic receptor stimulation that is independent from its capacity to inhibit TNF-alpha production.
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In recent investigations, high-mobility group box 1 (HMGB1) has been recognized to be an important factor in the development of sepsis. On the other hand, a serine protease inhibitor, nafamostat mesilate (NM) inhibits the enzyme activities of various protease and coagulation factors. We examined whether NM could inhibit HMGB1 in a rat sepsis model and thus could potentially be useful for treating sepsis. ⋯ Regarding the cell signal in each cell, we observed the inhibition of the phosphorylation of IkappaB. We thus concluded that it is possible to prevent the occurrence of pulmonary disorders in an endotoxic shock model by administering NM, however, this also inhibits the cell signal in a cell, mainly by the phosphorylation of IkappaB, thereby inhibiting the HMGB1 levels. Our findings thus suggest that the administration of NM may therefore potentially improve the condition of patients who have septic shock.