Smedegård G, Cui L X, Hugli T E
Department of Inflammation Research, Pharmacia AB, Uppsala, Sweden.
Am J Pathol. 1989 Sep;135(3):489-97.
Administration of endotoxin from gram-negative bacteria to rats results in systemic hypotension, an increased hematocrit, and decreased numbers of circulating leukocytes (polymorphonuclear), monocytes, and platelets. These potentially lethal physiologic changes may be partially attributed to complement activation and generation of anaphylatoxins by the endotoxin (LPS). We demonstrated an elevation in the plasma levels of both C3a and C5a in LPS-treated rats. Injection of 5 micrograms C5ades Arg (rat) into rats produced effects similar to those induced by LPS, including decreased mean arterial pressure (systemic hypotension) and decreased numbers of circulating polymorphonuclear leukocytes, monocytes, and platelets. Unlike the response to LPS, C5a did not increase the hematocrit, indicating little effect on vascular permeability at the doses used. When LPS-treated animals were pretreated with F(ab')2 fragments of rabbit anti-rat C5a, no changes were measured in the circulating cell counts compared with LPS alone; however a significant improvement in the mean arterial pressure and a decrease in hematocrit was observed. We conclude that LPS-induced (septic) shock in the rat may result, in part, from the effects of complement activation and particularly from the generation of C5a. The influence of C5a on the LPS effect in the rat appears to enhance both the hypotensive (mean arterial pressure) and vascular permeability (hematocrit) responses. These results appear to support and confirm earlier observations that anti-human C5a increased survival in a septic-shock monkey model by eliminating circulating C5a and presumably thereby reducing the effects of endotoxin on blood pressure. Our results demonstrate that C5a plays a significant role in the hemodynamic changes associated with endotoxin-induced shock. Neutralization of C5a with specific antibodies may reduce the hypotensive response to endotoxin sufficiently to prevent lethal septic shock both in animals and in man.
给大鼠注射革兰氏阴性菌内毒素会导致全身性低血压、血细胞比容升高以及循环白细胞（多形核白细胞）、单核细胞和血小板数量减少。这些潜在的致命生理变化可能部分归因于补体激活以及内毒素（脂多糖，LPS）产生过敏毒素。我们证明了LPS处理的大鼠血浆中C3a和C5a水平均升高。给大鼠注射5微克C5ades Arg（大鼠）产生的效应与LPS诱导的效应相似，包括平均动脉压降低（全身性低血压）以及循环多形核白细胞、单核细胞和血小板数量减少。与对LPS的反应不同，C5a不会增加血细胞比容，表明在所使用的剂量下对血管通透性影响很小。当用兔抗大鼠C5a的F(ab')2片段预处理LPS处理的动物时，与单独使用LPS相比，循环细胞计数没有变化；然而，观察到平均动脉压有显著改善且血细胞比容降低。我们得出结论，大鼠中LPS诱导的（脓毒性）休克可能部分是由于补体激活的作用，特别是C5a的产生。C5a对大鼠中LPS效应的影响似乎增强了低血压（平均动脉压）和血管通透性（血细胞比容）反应。这些结果似乎支持并证实了早期的观察结果，即抗人C5a通过消除循环中的C5a并推测从而减少内毒素对血压的影响，提高了脓毒性休克猴模型的存活率。我们的结果表明，C5a在与内毒素诱导的休克相关的血流动力学变化中起重要作用。用特异性抗体中和C5a可能充分降低对内毒素的低血压反应，以预防动物和人类的致命性脓毒性休克。
