Mathison J C, Wolfson E, Ulevitch R J
Department of Immunology, Research Institute of Scripps Clinic, La Jolla, California 92037.
J Clin Invest. 1988 Jun;81(6):1925-37. doi: 10.1172/JCI113540.
Macrophages are induced by LPS to release a number of products that determine the host response during gram negative sepsis. To examine the role of one such substance, tumor necrosis factor (TNF), in mediating LPS-induced injury, we employed a rabbit model of endotoxic shock to (a) determine the kinetics and extent of release of TNF into plasma after injection of LPS, and (b) to evaluate the protective effect of in vivo neutralization of LPS-induced TNF by prior infusion of anti-TNF antibody. TNF was maximally induced 45-100 min after injection of 10 micrograms i.v. parent Salmonella minnesota Re595 LPS or 250 micrograms Re595 LPS-HDL complexes. Maximal induction of TNF by LPS was associated with development of hypotension, focal hepatic necrosis, intravascular fibrin deposition and lethality. Based on (a) the peak levels of TNF observed in serum, 2.5 X 10(3) U/ml, (b) the specific activity of purified rabbit macrophage-derived TNF, 1 X 10(8) U/mg, and (c) the biphasic disappearance of intravenously injected purified TNF (t1/2 = 0.5 min, 11 min) we constructed a kinetic model showing that at least 130 micrograms of TNF (1.3 X 10(7) U) was released into plasma 30-200 min postinjection of LPS. Prior infusion of anti-TNF antibody (30-45 min before LPS injection) resulted in neutralization of the LPS-induced serum TNF activity and provided significant protection from the development of hypotension, fibrin deposition, and lethality. Thus, these results provide further evidence that TNF plays a central role mediating the pathophysiologic changes that occur during gram negative endotoxic shock.
脂多糖可诱导巨噬细胞释放多种产物，这些产物决定了革兰氏阴性菌败血症期间的宿主反应。为了研究其中一种物质——肿瘤坏死因子（TNF）在介导脂多糖诱导的损伤中的作用，我们采用了内毒素休克兔模型来：（a）确定注射脂多糖后TNF释放到血浆中的动力学和程度，以及（b）评估预先输注抗TNF抗体对体内中和脂多糖诱导的TNF的保护作用。静脉注射10微克亲本明尼苏达沙门氏菌Re595脂多糖或250微克Re595脂多糖 - 高密度脂蛋白复合物后45 - 100分钟，TNF被最大程度诱导。脂多糖对TNF的最大诱导与低血压、局灶性肝坏死、血管内纤维蛋白沉积和致死率的发展相关。基于（a）血清中观察到的TNF峰值水平，2.5×10³ U/ml，（b）纯化的兔巨噬细胞源性TNF的比活性，1×10⁸ U/mg，以及（c）静脉注射纯化TNF的双相消失（t1/2 = 0.5分钟，11分钟），我们构建了一个动力学模型，表明在注射脂多糖后30 - 200分钟内至少有130微克的TNF（1.3×10⁷ U）释放到血浆中。预先输注抗TNF抗体（在注射脂多糖前30 - 45分钟）导致脂多糖诱导的血清TNF活性被中和，并显著保护动物免受低血压、纤维蛋白沉积和致死率的发展。因此，这些结果进一步证明TNF在介导革兰氏阴性菌内毒素休克期间发生的病理生理变化中起核心作用。
