Institute of Pathology, Southwest Hospital, Third Military Medical University, Chongqing, China.
Front Biosci (Landmark Ed). 2014 Jun 1;19(6):904-15. doi: 10.2741/4256.
Sepsis continues to be a leading cause of intensive care unit (ICU) death. Gram-negative bacteria are among the most important pathogens of sepsis and their LPS content is regarded to be an important stimulator that elicits the systemic inflammatory reaction. MD-2 is a small secreted glycoprotein that can bind to both the hydrophobic portion of LPS and to the extracellular domain of TLR4. The interaction between MD-2 and LPS bridges the two TLR4 molecules and induces the dimerization of LPS-MD-2-TLR4, which forms the structural basis for biological functions of TLR4/MD-2 complex. Due to its essential role in mediating the interaction between LPS and TLR4, MD-2 has been extensively explored as a therapeutic target for treatment of inflammatory disorders such as sepsis. Eritoran is a synthetic tetraacylated lipid A that binds directly to MD-2 and antagonizes LPS binding to the same site. Although eritoran showed positive results in phase I and phase II clinical trials of severe sepsis, a phase III clinical study for severe sepsis has failed. More effective therapeutic strategies are in need to treat this devastating clinical disorder.
败血症仍然是重症监护病房（ICU）死亡的主要原因。革兰氏阴性菌是败血症最重要的病原体之一，其 LPS 含量被认为是引发全身炎症反应的重要刺激物。MD-2 是一种小分泌糖蛋白，可与 LPS 的疏水区和 TLR4 的细胞外结构域结合。MD-2 和 LPS 之间的相互作用连接了两个 TLR4 分子，并诱导 LPS-MD-2-TLR4 的二聚化，这形成了 TLR4/MD-2 复合物的生物学功能的结构基础。由于其在介导 LPS 和 TLR4 相互作用中的重要作用，MD-2 已被广泛探索作为治疗败血症等炎症性疾病的治疗靶点。Eritoran 是一种合成的四酰化脂 A，可直接与 MD-2 结合并拮抗 LPS 与同一部位的结合。尽管 Eritoran 在严重败血症的 I 期和 II 期临床试验中显示出积极的结果，但严重败血症的 III 期临床试验失败。需要更有效的治疗策略来治疗这种破坏性的临床疾病。
