Jesmok G, Lindsey C, Duerr M, Fournel M, Emerson T
Miles Research Center, Miles Inc., West Haven, Connecticut 06516.
Am J Pathol. 1992 Nov;141(5):1197-207.
Monoclonal antibody against human tumor necrosis factor alpha (TNF MAb) prevents death induced by intravenous gram-negative bacteria or lipopolysaccharide (LPS) in primates. Although these studies have demonstrated that TNF plays a prominent role in the development of lethal septic shock, exploration of dose-response relationships and possible mechanisms of protection have been limited. We addressed these questions in a series of experiments conducted in E. coli-challenged pigs. First, we determined that TNF MAb neutralized the cytotoxic activity found in septic pig plasma and in culture media from pig monocytes incubated with LPS. Second, we demonstrated that pretreatment with TNF MAb promotes survival, in a dose-dependent fashion, in an otherwise lethal E. coli bacteremic pig model. The results of the survival study highly correlate (r = 0.96, P < 0.01) the presence of TNF in the circulation with mortality. In an additional series of physiologic monitoring experiments designed to delineate possible mechanisms of protection, the authors demonstrate that TNF MAb pretreatment abrogates the prolonged leukopenia, thrombocytopenia, and microvascular leakiness resulting from intravenous bacterial challenge and maintains arterial blood pressure while diminishing pulmonary edema. These findings may provide a mechanism whereby neutralization of TNF systemically affords protection against the lethal sequelae of bacteremia.
抗人肿瘤坏死因子α单克隆抗体（TNF单克隆抗体）可预防灵长类动物因静脉注射革兰氏阴性菌或脂多糖（LPS）所致的死亡。尽管这些研究表明TNF在致死性脓毒性休克的发展中起重要作用，但对剂量反应关系和可能的保护机制的探索一直有限。我们在一系列用大肠杆菌攻击的猪身上进行的实验中解决了这些问题。首先，我们确定TNF单克隆抗体可中和脓毒症猪血浆以及与LPS一起孵育的猪单核细胞培养基中的细胞毒活性。其次，我们证明，在原本致死的大肠杆菌菌血症猪模型中，用TNF单克隆抗体预处理可促进存活，且呈剂量依赖性。存活研究结果表明，循环中TNF的存在与死亡率高度相关（r = 0.96，P < 0.01）。在另一系列旨在阐明可能保护机制的生理监测实验中，作者证明，TNF单克隆抗体预处理可消除静脉注射细菌攻击所致的持续性白细胞减少、血小板减少和微血管渗漏，并维持动脉血压，同时减轻肺水肿。这些发现可能提供了一种机制，即全身中和TNF可提供针对菌血症致死后遗症的保护。
