Reduced synthesis of inflammatory cytokines by a free radical scavenger after hemorrhagic shock in rats

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Abstract
Intestinal ischemia/reperfusion during hemorrhage and resuscitation may be a major trigger for cytokine expression. To assess whether free radicals produced on tissue reperfusion may play a role in the inflammatory response after hemorrhage, we tested the effect of a free radical scavenger on the production of inflammatory cytokines in a rat model of hemorrhagic shock. A prospective, controlled animal study. A university research laboratory. Male Wistar rats. Hemorrhage was induced in anesthetized rats. by bleeding the animal to achieve a mean arterial blood pressure of 40 mm Hg for 60 mins. Resuscitation was then induced by reinjecting shed blood followed by NaCl 0.9% to maintain arterial blood pressure within control values. Treated rats received the free radical scavenger N-2-mercaptopropionyl glycine (MPG; 20mg/kg iv bolus 30 mins before resuscitation followed by 20 mg/kg/hr). MPG reduced the volume of saline necessary to restore blood pressure during resuscitation (untreated 85 ± 6; MPG 35 ± 5 mL/kg;p < .05). As compared with untreated rats, MPG markedly reduced the systemic and mesenteric plasma concentrations of tumor necrosis factor (TNF)-α (as measured by ELISA) and interleukin (IL)-6 (as measured by bioassay), assessed at the end of resuscitation. MPG also reduced TNF-α and IL-6 mRNA expression (as measured by reverse transcriptase-polymerase chain reaction) assessed in peritoneal macrophages isolated from shock rats. Finally, in vitro experiments showed that MPG also markedly reduced the mRNA expression and release of TNF-α and IL-6 in peritoneal macrophages isolated from normal rats and subjected to hypoxia and reoxygenation. Reactive oxygen species contribute to the production of proinflammatory cytokines during posthemorrhage resuscitation. Free radicals scavengers may be a useful treatment in the prevention of the systemic inflammatory response that occurs in shock states.