Tschaikowsky K, Brain J D
Department of Environmental Science and Physiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Shock. 1994 Jun;1(6):401-7. doi: 10.1097/00024382-199406000-00002.
Bacterial lipopolysaccharide (LPS) can elicit septic shock; however, there is growing evidence that most of its pathophysiological effects are mediated by the release of tumor necrosis factor (TNF) and other cytokines. In turn, LPS-induced TNF production is thought to implicate the activation of intracellular protein kinase C (PKC). In this study, we examined whether pH-sensitive liposomes containing staurosporine (STP), a potent inhibitor of PKC, when injected intravenously would suppress TNF production and reduce mortality in an endotoxin rat model. We found that pretreatment of rats with pH-sensitive STP-liposomes by intravenous administration 1.5 h prior to LPS injection decreased lethality from 80% to approximately 30%. Importantly, this improvement in outcome was associated with significant reductions in TNF serum levels; 1 h after LPS injection serum TNF was 73% lower than in a saline control group, and at 2 h TNF levels were 84% lower. STP-liposome pretreatment also ameliorated the severe reduction in body temperature, characteristic for a hypodynamic shock, that was observed in LPS-challenged rats, but had relatively little effect on the transient leukopenia. We conclude that STP-liposomes can suppress LPS-induced TNF production by the mononuclear phagocytic system, can reduce the symptoms of septic shock, and can increase survival.
细菌脂多糖（LPS）可引发感染性休克；然而，越来越多的证据表明，其大多数病理生理效应是由肿瘤坏死因子（TNF）和其他细胞因子的释放介导的。反过来，LPS诱导的TNF产生被认为与细胞内蛋白激酶C（PKC）的激活有关。在本研究中，我们检测了静脉注射含有PKC强效抑制剂星形孢菌素（STP）的pH敏感脂质体是否会抑制TNF产生并降低内毒素大鼠模型的死亡率。我们发现，在注射LPS前1.5小时通过静脉给药对大鼠进行pH敏感的STP脂质体预处理，可使致死率从80%降至约30%。重要的是，这种结果的改善与TNF血清水平的显著降低相关；LPS注射后1小时，血清TNF比生理盐水对照组低73%，2小时时TNF水平低84%。STP脂质体预处理还改善了LPS攻击大鼠中观察到的体温严重降低，这是低动力性休克的特征，但对短暂性白细胞减少的影响相对较小。我们得出结论，STP脂质体可抑制单核吞噬系统中LPS诱导的TNF产生，可减轻感染性休克症状，并可提高存活率。
