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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Anesthetics used in burn and trauma animal models may be influencing results by modulating inflammatory and acute-phase responses. Accordingly, we determined the effects of various anesthetics, analgesia, and euthanasia techniques in a rodent burn model. Isoflurane (ISO), ketamine-xylazine (KX), or pentobarbital (PEN) with or without buprenorphine were administered before scald-burn in 72 rats that were euthanized without anesthesia by decapitation after 24 h and compared with unburned shams. ⋯ Our findings indicate that brief anesthesia with ISO immediately before euthanasia by decapitation exerted the least dampening effect on the cytokines measured. Conversely, KX with buprenorphine may offer a better balance during longer procedures to avoid significant modulation. Standardization across all experiments that are compared and awareness of these findings are essential for those investigating the pathophysiology of inflammation in animal models.
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It has been proposed that vasodilatory therapy may increase microcirculatory blood flow and improve tissue oxygenation in septic shock. The authors aimed to evaluate the effects of levosimendan in systemic and splanchnic hemodynamics in a porcine model of septic shock in a randomized animal controlled study. This study was performed in an animal research facility in a university hospital. ⋯ Systemic blood pressure and vascular resistance did not differ as compared with the septic untreated group. Responses to noradrenaline significantly improved in animals treated with levosimendan. Treatment with levosimendan in this animal model of sepsis attenuated pulmonary vasoconstriction and improved portal blood flow, intestinal mucosal oxygenation, pulmonary function, and vascular reactivity.
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Intestinal ischemia-reperfusion (I/R) injury may cause acute systemic and lung inflammation. Here, we revisited the role of TNF-alpha in an intestinal I/R model in mice, showing that this cytokine is not required for the local and remote inflammatory response upon intestinal I/R injury using neutralizing TNF-alpha antibodies and TNF ligand-deficient mice. We demonstrate increased neutrophil recruitment in the lung as assessed by myeloperoxidase activity and augmented IL-6, granulocyte colony-stimulating factor, and KC levels, whereas TNF-alpha levels in serum were not increased and only minimally elevated in intestine and lung upon intestinal I/R injury. ⋯ In fact, the inflammatory lung response is dramatically reduced in TLR2/4-deficient mice, confirming an important role of TLR receptor signaling causing the inflammatory lung response. In conclusion, endogenous TNF-alpha is not or minimally elevated and plays no role as a mediator for the inflammatory response upon ischemic tissue injury. By contrast, TLR2/4 signaling induces an orchestrated cytokine/chemokine response leading to local and remote pulmonary inflammation, and therefore disruption of TLR signaling may represent an alternative therapeutic target.
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Comparative Study
Effects of a selective iNOS inhibitor versus norepinephrine in the treatment of septic shock.
Inhibition of NOS is not beneficial in septic shock; selective inhibition of the inducible form (iNOS) may represent a better option. We compared the effects of the selective iNOS inhibitor BYK191023 with those of norepinephrine (NE) in a sheep model of septic shock. Twenty-four anesthetized, mechanically ventilated ewes received 1.5 g/kg body weight of feces into the abdominal cavity to induce sepsis. ⋯ Survival times were similar in the three groups. In this model of peritonitis, selective iNOS inhibition had more beneficial effects than NE on pulmonary artery pressures, gas exchange, mesenteric blood flow, microcirculation, and lactate concentration. Combination of this selective iNOS inhibitor with NE allowed a higher arterial pressure and renal blood flow to be maintained.
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Vascular hyperpermeability is a clinical complication associated with hemorrhagic shock (HS) and occurs mainly because of the disruption of the adherens junctional complex. The objective of this study was to understand the role of 17beta-estradiol in HS-induced hyperpermeability particularly focusing on estrogen receptors. In male Sprague-Dawley rats, HS was induced by withdrawing blood to reduce the mean arterial pressure to 40 mmHg for 1 hour followed by 1 hour of resuscitation to 90 mmHg. ⋯ Tamoxifen 5 mg/kg attenuated HS-induced hyperpermeability, whereas 10 mg/kg induced permeability (P < 0.05). Both alpha and beta estrogen receptor agonists inhibited HS-induced hyperpermeability (P < 0.05). 17beta-Estradiol decreased HS-induced reactive oxygen species formation and restored mitochondrial transmembrane potential. 17beta-Estradiol decreased both cytosolic cytochrome c level and activation of caspase-3 (P < 0.05). These findings suggest that 17beta-estradiol protects the microvasculature after HS, and that this protection may be mediated through the alpha and beta estrogen receptors.