Netea M G, Demacker P N, Kullberg B J, Jacobs L E, Verver-Jansen T J, Boerman O C, Stalenhoef A F, Van der Meer J W
Division of General Internal Medicine, Department of Medicine, University Hospital Nijmegen, 6500 HB Nijmegen, The Netherlands.
Cytokine. 1998 Oct;10(10):766-72. doi: 10.1006/cyto.1998.0364.
Lipoproteins are able to bind to lipopolysaccharide (LPS) and neutralize its deleterious effects. However, it is not clear why the LPS-binding capacity of circulating lipoproteins, which is 10- to 10 000-fold above the maximal LPS concentrations found in septic patients, is not sufficient to inhibit the effects of LPS during an infection, whereas infusion of exogenous lipoproteins has a potent inhibitory action. In this study, the kinetics of LPS-neutralization by VLDL, LDL, and HDL were investigated, at lipoprotein-to-LPS ratios found in severe Gram-negative sepsis. At least 4-8-h preincubation of LPS with either LDL or HDL were necessary to inhibit 50% of the LPS-induced TNF-alpha production by human peripheral blood mononuclear cells (PBMC), whereas after 24 h of preincubation LDL or HDL strongly inhibited the TNF-alpha synthesis (70-90%, P<0.01). VLDL was the least effective lipoprotein fraction. In contrast, FITC-LPS bound to PBMC much more rapidly, with 70% of the total binding after 30 min, and 90% after 1-h incubation. The increase of LDL or HDL concentrations up to 10-fold (as in experimental models of hyperlipoproteinaemia) was able not only to further decrease TNF-alpha production after long LPS-lipoproteins preincubation periods, but also to improve the kinetics of LPS neutralization. In conclusion, LPS binds and stimulates the mononuclear cells in circulation before neutralization by endogenous lipoproteins can occur. Additional increase in the lipoprotein-to-LPS molar ratio (e.g. by infusion of exogenous lipoproteins) accelerates the kinetics of LPS neutralization, and may be useful as adjunctive therapy in severe Gram-negative infections.
脂蛋白能够结合脂多糖（LPS）并中和其有害作用。然而，尚不清楚为什么循环脂蛋白的LPS结合能力比脓毒症患者中发现的最大LPS浓度高10至10000倍，却不足以在感染期间抑制LPS的作用，而输注外源性脂蛋白却具有强大的抑制作用。在本研究中，研究了在严重革兰氏阴性脓毒症中发现的脂蛋白与LPS比例下，极低密度脂蛋白（VLDL）、低密度脂蛋白（LDL）和高密度脂蛋白（HDL）对LPS的中和动力学。LPS与LDL或HDL至少预孵育4至8小时，才能抑制人外周血单核细胞（PBMC）中50%的LPS诱导的肿瘤坏死因子-α（TNF-α）产生，而预孵育24小时后，LDL或HDL强烈抑制TNF-α的合成（70-90%，P<0.01）。VLDL是最无效的脂蛋白组分。相比之下，异硫氰酸荧光素标记的LPS（FITC-LPS）与PBMC的结合要快得多，孵育30分钟后总结合量的70%与之结合，孵育1小时后为90%。将LDL或HDL浓度提高至10倍（如在高脂蛋白血症实验模型中），不仅能够在LPS与脂蛋白长时间预孵育后进一步降低TNF-α的产生，还能改善LPS中和的动力学。总之，在LPS被内源性脂蛋白中和之前，它会先结合并刺激循环中的单核细胞。脂蛋白与LPS摩尔比的额外增加（例如通过输注外源性脂蛋白）可加速LPS中和的动力学，并且可能作为严重革兰氏阴性感染的辅助治疗方法。
