RECONSTITUTED HIGH-DENSITY LIPOPROTEINS IN A CANINE MODEL OF SEPTIC SHOCK

重构的高密度脂蛋白（R-HDL）已在体外显示， 在体内，具有抗内毒素特性。前提是 脂蛋白结合、中和和增加内毒素的清除。被 一种天然的生物产品，R-HDL可以被用于化学治疗， 预防高危患者和化疗诱导的感染性休克 中性粒细胞减少症，或在治疗上治疗败血性休克。为了验证这一 假设，在一项对照随机试验中，我们调查了 R-HDL对生存、内毒素血症、细胞因子产生的影响， 病理生理和代谢事件。 在植入E.犬大肠杆菌感染凝块 接受静脉内R-HDL对照脂质或人血清白蛋白（HSA）。 用R-HDL处理的动物具有较低水平的循环内毒素， 肿瘤坏死因子（TNF）和白色血细胞减少较小 与用脂质和HSA处理的动物相比，生存时间 脂质和HSA治疗的动物相似， 比R-HDL处理的动物的那些更好。R-HDL处理的动物 与血脂相比，肝功能异常显著更大， 和HSA处理的动物。在正常动物中，R-HDL引起短暂的 肝酶升高，在给予无菌凝块的动物中 腹膜内，R-HDL引起癫痫发作。因此，该R-HDL的制备 具有抗内毒素作用，但也具有肝脏和神经毒性。 我们现在计划研究一种不同的制备高密度 脂蛋白（HDL），其化学组成与 用于这个犬类实验这种新制剂是在 这种方法可以限制肝脏和神经毒性的可能性。 首先，我们将研究新的R-HDL制剂在小动物中的应用 活感染模型（大鼠），随后，如果没有毒性， 在我们的犬模型中， 败血性休克如果可以降低与R-HDL相关的毒性， 抗内毒素作用可能潜在地用于高 风险患者，或在治疗上用于已确诊的脓毒性 冲击.

Reconstituted high density lipoprotein (R-HDL) has been shown in vitro and in vivo, to have antiendotoxin properties. The hypothesis is that lipoproteins bind, neutralize, and increase clearance of endotoxin. Being a natural, biologic product, R-HDL could be used prophylactically, to prevent septic shock in high risk patients and in chemotherapy-induced neutropenia, or therapeutically to treat septic shock. To test this hypothesis, in a controlled, randomized trial, we investigated the effects of R-HDL on survival, endotoxemia, cytokine production, and pathophysiologic and metabolic events in our canine model of septic shock. At 0.5, 8, and 16 h after implantation of a E. coli infected clot, canines received intravenous R-HDL control lipid, or human serum albumin (HSA). Animals treated with R-HDL had lower levels of circulating endotoxin and tumor necrosis factor (TNF) and a smaller decrease in white blood cell counts than did animals treated with lipids and HSA. Survival times of lipid- and HSA-treated animals were similar and were significantly greater than those of R-HDL treated animals. R-HDL-treated animals had significantly greater abnormalities in liver function compared to lipid- and HSA-treated animals. In normal animals, R-HDL caused transient elevation of liver enzymes, and in animals given sterile clot intraperitoneally, R-HDL caused seizures. Thus, this preparation of R-HDL had antiendotoxin effects but also had hepatic and neurologic toxicities. We now plan to investigate a different preparation of high density lipoprotein (HDL) which has a different chemical composition than that used in this canine experiment. This new preparation was manufactured in such a way to limit the potential of liver and neurological toxicity. First, we will investigate the new R-HDL preparation in small animal models of live infection (rats), and subsequently, if no toxicity and beneficial antiendotoxin effects are documented, in our canine model of septic shock. If toxicities associated with R-HDL can be reduced, its antiendotoxin effects may potentially be used prophylactically in high risk patients, or therapeutically in patients with established septic shock.