Marra M N, Wilde C G, Collins M S, Snable J L, Thornton M B, Scott R W
Incyte Pharmaceuticals, Palo Alto, CA 94304.
J Immunol. 1992 Jan 15;148(2):532-7.
Systemic release of endotoxin (LPS) after Gram-negative infection initiates a cascade of host cytokines that are thought to be the direct cause of shock, multisystem organ failure, and death. Endogenous LPS-binding proteins may play a role in regulating LPS toxicity in vivo. The human neutrophil granule protein bactericidal/permeability-increasing protein (BPI) shares sequence homology and immunocrossreactivity with an acute phase lipopolysaccharide binding protein (LBP) which has been shown to bind to LPS and accelerate LPS activation of neutrophils and macrophages. Although structurally similar, LBP and BPI are apparently functionally antagonistic. We previously showed that BPI inhibits LPS-mediated neutrophil activation in vitro. Here we demonstrate that BPI binds to LPS near the lipid A domain, and formation of the LPS-BPI complex abrogates detrimental host responses to LPS. For example, BPI blocks LPS-stimulated TNF release in vitro and in vivo, and LPS complexed to BPI is not pyrogenic in rabbits. Results demonstrating that BPI is released by stimulated human neutrophils further support the idea that BPI functions extracellularly in vivo to neutralize endotoxin. Taken together, these data argue that BPI neutralizes the toxic effects of LPS in vivo, and that BPI may represent a new therapeutic approach to the treatment of endotoxic shock.
革兰氏阴性菌感染后内毒素（LPS）的全身释放引发了一系列宿主细胞因子的产生，这些细胞因子被认为是休克、多系统器官衰竭和死亡的直接原因。内源性LPS结合蛋白可能在体内调节LPS毒性方面发挥作用。人类中性粒细胞颗粒蛋白杀菌/通透性增加蛋白（BPI）与急性期脂多糖结合蛋白（LBP）具有序列同源性和免疫交叉反应性，后者已被证明可与LPS结合并加速LPS对中性粒细胞和巨噬细胞的激活。尽管LBP和BPI在结构上相似，但它们在功能上显然是拮抗的。我们之前表明BPI在体外可抑制LPS介导的中性粒细胞激活。在此我们证明BPI在脂质A结构域附近与LPS结合，并且LPS - BPI复合物的形成消除了宿主对LPS的有害反应。例如，BPI在体外和体内均可阻断LPS刺激的TNF释放，并且与BPI复合的LPS在兔子体内不具有致热原性。表明BPI由受刺激的人类中性粒细胞释放的结果进一步支持了BPI在体内细胞外发挥功能以中和内毒素的观点。综上所述，这些数据表明BPI在体内可中和LPS的毒性作用，并且BPI可能代表了一种治疗内毒素休克的新治疗方法。
