Bench-to-bedside review: The inflammation-perpetuating pattern-recognition receptor RAGE as a therapeutic target in sepsis.
Bench-to-bedside review: The inflammation-perpetuating pattern-recognition receptor RAGE as a therapeutic target in sepsis.
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DOI：
10.1186/cc6164
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Weigand MA
中科院分区：
文献类型：
--
作者：
Bopp C;Bierhaus A;Hofer S;Bouchon A;Nawroth PP;Martin E;Weigand MA
脓毒症仍然是重症监护病房面临的一个重要的临床和经济挑战。死亡率高的多器官衰竭等严重并发症以及缺乏特定的诊断工具继续阻碍脓毒症改良疗法的开发。有关实验和临床脓毒症细胞发病机制的基本问题仍未解决。根据实验数据，抑制巨噬细胞迁移抑制因子、高迁移率族盒蛋白1（HMGB1）和补体因子C5a以及抑制TREM-1（骨髓细胞表达的触发受体1）信号通路和凋亡代表了有前途的新治疗选择。此外，我们还证明，阻断晚期糖基化终末产物受体（RAGE）（一种新的炎症持续性受体，也是免疫球蛋白超家族的成员）的信号转导途径，可以提高实验性脓毒症的存活率。高级糖基化终产物、S100 和 HMGB1 激活 RAGE 会启动核因子 kappa B 和丝裂原激活蛋白激酶途径。重要的是，在盲肠结扎穿刺（CLP）感染性休克模型中，RAGE 敲除小鼠的存活率是野生型小鼠的四倍多。此外，应用可溶性 RAGE（RAGE 配体的细胞外诱饵）可提高 CLP 后小鼠的存活率，这表明 RAGE 在维持先天免疫反应中发挥着核心作用。了解这种多配体受体触发的基本信号转导事件可能为脓毒症患者提供新的诊断和治疗选择。
Sepsis still represents an important clinical and economic challenge for intensive care units. Severe complications like multi-organ failure with high mortality and the lack of specific diagnostic tools continue to hamper the development of improved therapies for sepsis. Fundamental questions regarding the cellular pathogenesis of experimental and clinical sepsis remain unresolved. According to experimental data, inhibiting macrophage migration inhibitory factor, high-mobility group box protein 1 (HMGB1), and complement factor C5a and inhibiting the TREM-1 (triggering receptor expressed on myeloid cells 1) signaling pathway and apoptosis represent promising new therapeutic options. In addition, we have demonstrated that blocking the signal transduction pathway of receptor of advanced glycation endproducts (RAGE), a new inflammation-perpetuating receptor and a member of the immunglobulin superfamily, increases survival in experimental sepsis. The activation of RAGE by advanced glycation end-products, S100, and HMGB1 initiates nuclear factor kappa B and mitogen-activated protein kinase pathways. Importantly, the survival rate of RAGE knockout mice was more than fourfold that of wild-type mice in a septic shock model of cecal ligation and puncture (CLP). Additionally, the application of soluble RAGE, an extracellular decoy for RAGE ligands, improves survival in mice after CLP, suggesting that RAGE is a central player in perpetuating the innate immune response. Understanding the basic signal transduction events triggered by this multi-ligand receptor may offer new diagnostic and therapeutic options in patients with sepsis.
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