Molnar R G, Wang P, Chaudry I H
Department of Surgery, Michigan State University, East Lansing, Michigan, 48824, USA.
J Surg Res. 1998 Nov;80(1):75-9. doi: 10.1006/jsre.1998.5343.
Although previous studies have indicated that hepatocellular dysfunction during early sepsis can be prevented by prior neutrophil depletion, it remains unknown whether the changes in hepatic oxidative stress induced by activated neutrophils are responsible for the salutary effect of neutropenia on hepatocellular function.
Neutropenia was induced in the rat by intravenous injection of immunoglobulins directly against rat neutrophils (anti-neutrophil Ig) at 16 and 2 h prior to the initiation of cecal ligation and puncture (CLP, i.e., an animal model of polymicrobial sepsis) or sham operation. Neutropenia was confirmed by peripheral blood smears. Neutrophil-competent control animals were given nonimmunized Ig prior to the onset of sepsis. Sham animals received anti-neutrophil Ig or control Ig. The levels of reduced glutathione (GSH) and oxidized glutathione (GSSG) in the liver were determined at 5 h after CLP (i.e., the early, hyperdynamic stage of sepsis) or sham operation by high performance liquid chromatography.
Although the levels of hepatic GSH and GSSG decreased significantly at 5 h after CLP, irrespective of neutropenia, the ratio of GSSG/GSH was not significantly altered under such conditions. The decrease in hepatic glutathione concentrations in septic animals may represent the decreased synthesis or increased efflux into the bile or circulation.
Since neutrophil depletion did not significantly affect hepatic levels of GSH and GSSG as well as the GSSG/GSH ratio but prevented the occurrence of hepatocellular dysfunction, factors other than oxidative stress are likely to be the mechanism responsible for depressing hepatocellular function during the early, hyperdynamic stage of sepsis.
尽管先前的研究表明，早期脓毒症期间的肝细胞功能障碍可通过预先耗尽中性粒细胞来预防，但由活化的中性粒细胞诱导的肝脏氧化应激变化是否是中性粒细胞减少对肝细胞功能有益作用的原因仍不清楚。
在盲肠结扎和穿刺（CLP，即多微生物脓毒症动物模型）或假手术开始前16小时和2小时，通过静脉注射直接针对大鼠中性粒细胞的免疫球蛋白（抗中性粒细胞Ig）诱导大鼠中性粒细胞减少。通过外周血涂片确认中性粒细胞减少。有中性粒细胞功能的对照动物在脓毒症发作前给予未免疫的Ig。假手术动物接受抗中性粒细胞Ig或对照Ig。在CLP（即脓毒症的早期、高动力阶段）或假手术后5小时，通过高效液相色谱法测定肝脏中还原型谷胱甘肽（GSH）和氧化型谷胱甘肽（GSSG）的水平。
尽管CLP后5小时肝脏中GSH和GSSG的水平显著降低，与中性粒细胞减少无关，但在这种情况下GSSG/GSH的比值没有显著改变。脓毒症动物肝脏中谷胱甘肽浓度的降低可能代表合成减少或胆汁或循环中流出增加。
由于中性粒细胞减少并未显著影响肝脏中GSH和GSSG的水平以及GSSG/GSH的比值，但可预防肝细胞功能障碍的发生，因此氧化应激以外的因素可能是脓毒症早期高动力阶段肝细胞功能抑制的机制。
