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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Splanchnic artery occlusion (SAO) followed by reperfusion causes endothelial injury and inflammation which contribute to the pathophysiology of shock. We investigated the effects of pea seedling (Latyrus cicera) histaminase, known to afford protection against the deleterious effects of cardiac ischemia/reperfusion, given to rats subjected to SAO/reperfusion-induced splanchnic injury. Histaminase (80 IU kg, 15 min before reperfusion) significantly reduced the drop of blood pressure and high mortality rate caused by SAO/reperfusion. ⋯ As a result, histaminase led to a reduction of ileal cell apoptosis (caspase 3, terminal deoxynucleotidyltransferase-mediated UTP end labeling-positive cells). These results show that histaminase exerts a clear-cut protective effect in SAO/reperfusion-induced splanchnic injury, likely caused by oxidative catabolism of proinflammatory histamine and antioxidant effects resulting in hindrance of free radical-mediated tissue injury, endothelial dysfunction, and leukocyte recruitment. Thus, histaminase could be used therapeutically in intestinal ischemia.
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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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We have demonstrated that volatile anesthetics reduce inflammation after renal ischemia/reperfusion injury in vivo. As hyperactive uncontrolled inflammation can lead to mortality and morbidity during early sepsis, we questioned whether the volatile anesthetic isoflurane could reduce mortality and protect against sepsis induced renal and hepatic dysfunction. Mice were anesthetized with isoflurane or with pentobarbital and subjected to cecal ligation and puncture (CLP) to induce septic peritonitis. ⋯ Isoflurane-treated mice had lower plasma levels of TNF-alpha, KC, and IL-6. Isoflurane-anesthetized mice also had significantly prolonged and increased survival compared with pentobarbital-anesthetized mice. Therefore, isoflurane anesthesia conferred significant protection against renal and hepatic dysfunction and death after septic peritonitis and attenuated renal inflammation and apoptosis compared with pentobarbital anesthesia.
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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.