Simkova Vladislava, Baumgart Katja, Vogt Josef, Wachter Ulrich, Weber Sandra, Gröger Michael, Speit Günter, Radermacher Peter, Albuszies Gerd, Barth Eberhard
Sektion Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Universitätsklinikum, Ulm, Germany.
Shock. 2008 Nov;30(5):578-84. doi: 10.1097/SHK.0b013e31816a6e0f.
Besides excess cytokine and NO production, enhanced oxygen radical formation was referred to contribute to the impaired hepatic gluconeogenesis during sepsis or endotoxemia. Therefore, we tested the hypothesis that genetic overexpression of the Cu/Zn-superoxide dismutase (SOD-1) may restore the sepsis-related lack of the norepinephrine-induced increase in hepatic gluconeogenesis and whole-body glucose oxidation. Anesthetized, ventilated, and instrumented wild-type control, and heterozygous and homozygous SOD-1-overexpressing mice received hydroxyethyl starch and norepinephrine to maintain normotensive hemodynamics measured at 18, 21, and 24 h after cecal ligation and puncture (CLP) or sham operation. Hepatic gluconeogenesis and whole-body glucose oxidation were calculated from liver tissue isotope and expiratory 13CO2 enrichments during continuous i.v. 1,2,3,4,5,6-13C6-glucose. Superior mesenteric artery and portal vein flows (ultrasound flow probes) and hepatic microcirculatory perfusion (Laser Doppler flowmetry) and O2 saturation (remission spectrophotometry) were comparable in the CLP and sham-operated animals, without any difference related to the mouse strain. Despite continuous i.v. norepinephrine necessary in the CLP mice, both glycemia and hepatic gluconeogenesis were similar, irrespective of the presence of sepsis and the genetic strain. Glucose oxidation rate progressively increased in the CLP groups, again without difference between the genetic strains. The surgery- and CLP-induced increase in liver cell oxidative DNA damage (tail moment in the comet assay) was less pronounced in the homozygous mice. Heterozygous nor homozygous SOD-1 overexpression did not improve the sepsis-related impairment of carbohydrate metabolism, possibly because of the lacking increase of the tissue catalase and the mitochondrial SOD activity, and the ongoing i.v. norepinephrine.
除了细胞因子和一氧化氮产生过多外，氧自由基生成增加也被认为是导致脓毒症或内毒素血症期间肝糖异生受损的原因。因此，我们检验了以下假设：铜/锌超氧化物歧化酶（SOD-1）的基因过表达可能恢复脓毒症相关的去甲肾上腺素诱导的肝糖异生增加和全身葡萄糖氧化缺乏。对麻醉、通气并安装仪器的野生型对照小鼠、杂合子和纯合子SOD-1过表达小鼠给予羟乙基淀粉和去甲肾上腺素，以维持在盲肠结扎和穿刺（CLP）或假手术后18、21和24小时测得的正常血压血流动力学。在持续静脉输注1,2,3,4,5,6-13C6-葡萄糖期间，根据肝组织同位素和呼气13CO2富集情况计算肝糖异生和全身葡萄糖氧化。CLP组和假手术组动物的肠系膜上动脉和门静脉血流（超声血流探头）、肝微循环灌注（激光多普勒血流仪）和氧饱和度（发射分光光度法）相当，与小鼠品系无关。尽管CLP小鼠需要持续静脉输注去甲肾上腺素，但无论是否存在脓毒症和基因品系，血糖和肝糖异生均相似。CLP组的葡萄糖氧化率逐渐增加，基因品系之间同样没有差异。手术和CLP诱导的肝细胞氧化DNA损伤（彗星试验中的尾矩）在纯合子小鼠中不太明显。杂合子或纯合子SOD-1过表达并未改善脓毒症相关的碳水化合物代谢损害，这可能是由于组织过氧化氢酶和线粒体SOD活性缺乏增加，以及持续静脉输注去甲肾上腺素所致。
