Leturcq D J, Moriarty A M, Talbott G, Winn R K, Martin T R, Ulevitch R J
R.W. Johnson Pharmaceutical Research Institute, San Diego, California 92121, USA.
J Clin Invest. 1996 Oct 1;98(7):1533-8. doi: 10.1172/JCI118945.
Lipopolysaccharide (LPS), residing in the outer membrane of all gram-negative bacteria, is considered a major initiating factor of the gram-negative septic shock syndrome in humans. LPS forms a complex with the LPS binding protein (LBP) in plasma, and LPS-LBP complexes engage a specific receptor, CD14, on the surface of myeloid cells, leading to the production of potent proinflammatory cytokines. The major goal of this study was to test the importance of the CD14 pathway in vivo in a primate model that is similar to human septic shock. Primates were pretreated with one of two different inhibitory anti-CD14 mAbs, then challenged with intravenous endotoxin (375 microg/kg/h) for 8 h. The anti-CD14 treatment regimens were successful in preventing profound hypotension, reducing plasma cytokine levels (TNF-alpha, IL-1beta, IL-6, and IL-8), and inhibiting the alteration in lung epithelial permeability that occurred in animals treated with LPS and an isotype-matched control antibody. These results demonstrate for the first time the importance of the CD14 pathway in a primate model that is similar to human septic shock. Inhibition of the CD14 pathway represents a novel therapeutic approach to treating this life-threatening condition.
脂多糖（LPS）存在于所有革兰氏阴性菌的外膜中，被认为是人类革兰氏阴性菌败血症休克综合征的主要起始因素。LPS在血浆中与LPS结合蛋白（LBP）形成复合物，LPS-LBP复合物与髓样细胞表面的特异性受体CD14结合，导致产生强效促炎细胞因子。本研究的主要目的是在类似于人类败血症休克的灵长类动物模型中测试CD14途径在体内的重要性。用两种不同的抑制性抗CD14单克隆抗体之一预处理灵长类动物，然后静脉注射内毒素（375微克/千克/小时）8小时。抗CD14治疗方案成功预防了严重低血压，降低了血浆细胞因子水平（TNF-α、IL-1β、IL-6和IL-8），并抑制了用LPS和同型对照抗体治疗的动物中发生的肺上皮通透性改变。这些结果首次证明了CD14途径在类似于人类败血症休克的灵长类动物模型中的重要性。抑制CD14途径代表了一种治疗这种危及生命疾病的新方法。
