Department of Microbiology and Immunology, University of Maryland, Baltimore, Baltimore, Maryland 21201, USA.
Nature. 2013 May 23;497(7450):498-502. doi: 10.1038/nature12118. Epub 2013 May 1.
There is a pressing need to develop alternatives to annual influenza vaccines and antiviral agents licensed for mitigating influenza infection. Previous studies reported that acute lung injury caused by chemical or microbial insults is secondary to the generation of host-derived, oxidized phospholipid that potently stimulates Toll-like receptor 4 (TLR4)-dependent inflammation. Subsequently, we reported that Tlr4(-/-) mice are highly refractory to influenza-induced lethality, and proposed that therapeutic antagonism of TLR4 signalling would protect against influenza-induced acute lung injury. Here we report that therapeutic administration of Eritoran (also known as E5564)-a potent, well-tolerated, synthetic TLR4 antagonist-blocks influenza-induced lethality in mice, as well as lung pathology, clinical symptoms, cytokine and oxidized phospholipid expression, and decreases viral titres. CD14 and TLR2 are also required for Eritoran-mediated protection, and CD14 directly binds Eritoran and inhibits ligand binding to MD2. Thus, Eritoran blockade of TLR signalling represents a novel therapeutic approach for inflammation associated with influenza, and possibly other infections.
目前迫切需要开发替代每年接种流感疫苗和抗病毒药物的方法，这些疫苗和药物是为了减轻流感感染而获得许可的。先前的研究报告指出，化学或微生物刺激引起的急性肺损伤是宿主衍生的氧化磷脂产生的结果，氧化磷脂能强烈刺激 Toll 样受体 4（TLR4）依赖性炎症。随后，我们报告称 Tlr4(-/-) 小鼠对流感引起的致死性高度耐受，并提出治疗性拮抗 TLR4 信号转导将有助于预防流感引起的急性肺损伤。在这里，我们报告称，治疗性给予 Eritoran（也称为 E5564）——一种有效的、耐受性良好的合成 TLR4 拮抗剂——可阻断流感在小鼠中的致死性，以及肺部病理、临床症状、细胞因子和氧化磷脂的表达，并降低病毒滴度。CD14 和 TLR2 也是 Eritoran 介导的保护所必需的，CD14 直接结合 Eritoran 并抑制配体与 MD2 的结合。因此，Eritoran 阻断 TLR 信号转导代表了一种与流感相关的炎症的新型治疗方法，可能也与其他感染有关。
