Soluble MD-2 activity in plasma from patients with severe sepsis and septic shock
Soluble MD-2 activity in plasma from patients with severe sepsis and septic shock
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DOI：
10.1182/blood-2003-04-1290
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发表时间：
2004-12-15
期刊：
影响因子：
20.3
通讯作者：
Dunn-Siegrist, I
中科院分区：
文献类型：
--
作者：
Pugin, J;Stern-Voeffray, S;Dunn-Siegrist, I
在本文中，我们表明，来自严重脓毒症和脓毒性休克患者的血浆而非正常血浆支持表达 Toll 样受体 4 (TLR4) 的上皮细胞的脂多糖 (LPS) 激活。重组可溶性骨髓分化蛋白 2 (MD-2) 补充正常血浆，并使上皮细胞的 LIPS 激活达到“脓毒症”血浆测量的水平，而可溶性 MD-2 耗尽的血浆则失去其作用。在脓毒性休克患者的尿液和成人呼吸窘迫综合征 (ARDS) 患者的肺水肿液中也发现了相同的“MD-2 活性”。重组可溶性 MD-2 能够对带有 TLR4 的上皮细胞进行 LPS 依赖性激活。 LPS结合蛋白(LBP)和可溶性CD14增加了表达TLR4的上皮细胞对LIPS的敏感性，但在可溶性MD-2不存在的情况下不能介导这些细胞的LIPS活化。仅在脓毒症血浆或脓毒症尿液存在的情况下，抗 MD-2 单克隆抗体才能阻断 TLR4 表达细胞的 LPS 激活。这些结果表明，含有可溶性 MD-2 的脓毒血浆渗漏到血管外空间支持表达 TLR4 的上皮细胞的 LIPS 激活。因此，我们认为可溶性 MD-2 是脓毒症期间器官炎症的重要介质。
In this paper, we show that plasma from patients with severe sepsis and septic shock but not normal plasma supports lipopolysaccharide (LPS) activation of epithelial cells expressing Toll-like receptor 4 (TLR4). Recombinant soluble myeloid differentiation protein-2 (MD-2) complemented normal plasma and allowed LIPS activation of epithelial cells to levels measured with "septic" plasma, whereas soluble MD-2-depleted plasma lost its effects. The same "MD-2 activity" was found in urine from a patient with septic shock and in lung edema fluids from patients with adult respiratory distress syndrome (ARDS). Recombinant soluble MD-2 enabled LPS-dependent activation of epithelial cells bearing TLR4. LPS-binding protein (LBP) and soluble CD14 increased the sensitivity of TLR4-expressing epithelial cells to LIPS but were not able to mediate LIPS activation of these cells in the absence of soluble MD-2. An anti-MD-2 monoclonal antibody blocked LPS activation of TLR4-expressing cells only in the presence of septic plasma or septic urine. These results suggest that septic plasma containing soluble MD-2 leaking into the extravascular space supports LIPS activation of TLR4-expressing epithelial cells. We therefore propose that soluble MD-2 is an important mediator of organ inflammation during sepsis.