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백서패혈증 모델에서 Melatonin 항산화 효과에 관한 연구
홍성화,이상목,조용호,고영관,이석환,고석환,김윤화,윤충,김명천,백형환,변영훈 대한외상학회 1999 大韓外傷學會誌 Vol.12 No.1
Despite the major advances in the management of critically ill patients, septic shock and ensuing MODS continue to be the most common causes of death in the surgical intensive care unit. Endotoxin in sepsis stimulates macrophages and immune cells, and these stimulated cells secrete multiple cytokines such as TNF-α, IL-1β, and INFγ and these in turn stimulate polymorphonuclear leukocytes(PMNs). The stimulated PMNs easily adhere to the vascular endothelial wall and secrete free oxygen radicals, which destroy cell function by cellular membrane lipid peroxidation. The consecutive reactions are responsible for the pathophysiologic consequences of septic shock. Melatonin, the major endocrine product of the pineal gland, was found to be an effective free radical scavenger and antioxidant and may stimulate some important antioxidant enzymes, i.e. superoxide dismutase, glutathione peroxidase and glutathione reductase. This study focused on the effect of melatonin in rat sepsis model by using the Chaudry method, cecal ligation and puncture(CLP) that the cecum was ligated with 3-0 silk and punctured with 21-gauge needle twice. Rats were divided into 3 groups: the control group(Sham operation group), the ethanol-administered group, and the melatonin-administered group. There were eight rats in each group. Melatonin 10mg/kg was administered subcutaneously every one hour. Parameters to be checked were tumor necrosis factor(TNF-α) and IL-1β in rat serum and malondialdehyde(MDA), xanthine oxidase, and histopathologic findings in the lung and the liver. Each parameter was obtained 2, 4, 6 and 10 hours after operation by sacrificing the rats at that time. The concentration of TNF-α increased persistently in sepsis induced groups and was significantly lower (p$lt;0.05) 2 hours after operation in the melatonin-administered group (39.5 ±12.1pg/ml) than in the ethanol-administered group (82.0 ±9.1pg/ml) and was lower 4, 6, and 10 hours after operation in the melatonin-administered group, but this last data was not statistically significant. The concentration of IL-1β in the melatonin-administered group was lower than that of the ethanol- administered group, but this was not statistically significant. The concentration of MDA in the lung in the ethanol-administered and the melatonin-adminis- tered group at 10 hours after operation was 199.3 ±51.1 and 56.5 ±23.3 pmol/mg protein, respectively, which indicates a statisticaUy significant difference(ANOVA test, p$lt;0.001). The concentration of MDA in the liver 6 and 10 hours after operation in the ethanol-administered and melatonin-administemd groups was 260.6 ±38.5, 291.2 ±65.1 and 172.6 ±25.3, 148 ±9.1 pmoVmg protein, respectively, showing a statistically significant difference. There was more of an elevation in the concentration of xanthine oxidase in the lung and the liver of the ethanol- administered group, but it was statistically insignificant. Histopathologic findings of the lung in the melatonin-administered group 6 hours after operation showed intact alveoli and minimal infiltration of polymorphonuclear leukocytes in alveoli and interstitial thickening with many PMNs infiltrations and those of the liver in the melatonin-administered group showed less infiltration of PMNs in the portal space. In conclusion, melatonin was considered to have an antioxidant activity, a scavenging effect on free oxygen radical, and an inhibitory activity for an infiltration to the lung and the liver, especially in the early septic period. Further studies on the effect of a late septic period and the therapeutic dose of melatonin are needed.