Kawata T, Bristol J R, Rose J R, Rossignol D P, Christ W J, Asano O, Dubuc G R, Gavin W E, Hawkins L D, Kishi Y
Section of Biology, Eisai Research Institute, Andover, MA 01810-2441, USA.
Prog Clin Biol Res. 1995;392:499-509.
Lipid As from non-toxic bacteria such as Rhodobacter capsulatus and Rhodobacter sphaeroides have been shown to antagonize the immunostimulatory effects of lipid A and LPS from pathogenic bacteria. We have biologically characterized a series of synthetic LPS antagonists including the proposed structures of the lipid A and R. sphaeroides containing fatty acid side chains ester-linked to the disaccharide backbone, as well as an analog of R. capsulatus lipid A containing ether-linked alkyloxy side chains (E5531). In vitro assays utilizing LPS-stimulated human monocytes or whole blood demonstrated that low nanomolar concentrations of E5531 inhibited cellular activation as indicated by decreased release of the cytokines TNF-a, and interleukins-1, 6, and 8. E5531 also inhibited LPS-induced release of cytokines and nitric oxide from murine macrophages. Synthetic antagonists at up to 100 microM were devoid of agonistic activity in murine and human in vitro systems. In vivo, E5531 blocked induction of TNF-a by LPS and reduced LPS-induced lethality in mice. These in vitro and in vivo results indicate that E5531 may have clinical therapeutic utility as an antagonist of endotoxin-mediated morbidity and mortality.
来自无毒细菌（如荚膜红细菌和球形红细菌）的类脂A已被证明可拮抗病原菌的类脂A和脂多糖的免疫刺激作用。我们对一系列合成脂多糖拮抗剂进行了生物学特性分析，包括所提出的含有与二糖主链酯连接的脂肪酸侧链的类脂A和球形红细菌的结构，以及含有醚连接的烷氧基侧链的荚膜红细菌类脂A类似物（E5531）。利用脂多糖刺激的人单核细胞或全血进行的体外试验表明，低纳摩尔浓度的E5531可抑制细胞活化，这表现为细胞因子TNF-α以及白细胞介素-1、6和8的释放减少。E5531还可抑制脂多糖诱导的小鼠巨噬细胞释放细胞因子和一氧化氮。在小鼠和人类体外系统中，高达100微摩尔的合成拮抗剂没有激动活性。在体内，E5531可阻断脂多糖诱导的TNF-α的产生，并降低脂多糖诱导的小鼠致死率。这些体外和体内结果表明，E5531作为内毒素介导的发病和死亡的拮抗剂可能具有临床治疗效用。
