Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.
Innate Immun. 2012 Feb;18(1):171-8. doi: 10.1177/1753425910394395. Epub 2011 Mar 7.
Lipid A, the active moiety of LPS, exerts its effects through interaction with TLR4, triggering a signalling cascade that results in the release of pro-inflammatory cytokines. Eritoran is a lipid A analogue that competes with LPS for binding to TLR4; however, after intravenous administration, it undergoes a time-dependent deactivation as a consequence of binding to high-density lipoproteins (HDLs). The site of eritoran association with HDL remains unknown. Therefore the aim of this study was to determine if HDL-associated apolipoproteins A1, A2, serum amyloid A (SAA) and C1, inhibit the ability of eritoran to block LPS-induced TNF-α release from whole blood. Eritoran activity after LPS stimulation in human whole blood was assessed in the presence of reconstituted HDL (rHDL) containing different apos. In rHDL, the major apolipoproteins in both the healthy and septic state, A1 and SAA, caused a significant reduction in eritoran antagonistic activity and had a greater effect than minor apolipoproteins A2 and C1. Apolipoproteins associated with HDL are likely to facilitate eritoran deactivation. Apolipoproteins A1 and SAA should be of particular focus as they are the major apos found on HDL in both the healthy and septic state. Further evaluation of the physical association between apolipoproteins and eritoran should be explored.
脂质 A 是 LPS 的活性部分，通过与 TLR4 相互作用发挥作用，触发信号级联反应，导致促炎细胞因子的释放。Eritoran 是一种脂质 A 类似物，与 LPS 竞争与 TLR4 结合；然而，静脉给药后，由于与高密度脂蛋白 (HDL) 结合，它会发生时间依赖性失活。Eritoran 与 HDL 结合的部位尚不清楚。因此，本研究旨在确定 HDL 相关载脂蛋白 A1、A2、血清淀粉样蛋白 A (SAA) 和 C1 是否抑制 Eritoran 阻断 LPS 诱导的全血 TNF-α释放的能力。在存在含有不同载脂蛋白的重组 HDL (rHDL) 的情况下，评估 LPS 刺激后人类全血中 Eritoran 的活性。在 rHDL 中，健康和脓毒症状态下的主要载脂蛋白 A1 和 SAA 导致 Eritoran 拮抗活性显著降低，比次要载脂蛋白 A2 和 C1 的影响更大。与 HDL 相关的载脂蛋白可能促进 Eritoran 失活。载脂蛋白 A1 和 SAA 应该特别关注，因为它们是健康和脓毒症状态下 HDL 上主要的载脂蛋白。应进一步探索载脂蛋白与 Eritoran 之间的物理关联。
