Winkler Martin Sebastian, Märtz Konstantin B, Nierhaus Axel, Daum Günter, Schwedhelm Edzard, Kluge Stefan, Gräler Markus H
1Department of Anesthesiology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246 Germany.
6Department of Anesthesiology and Intensive Care Medicine, Universitätsmedizin Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany.
J Intensive Care. 2019 Apr 17;7:23. doi: 10.1186/s40560-019-0376-2. eCollection 2019.
Sphingosine 1-phosphate (S1P) is a signaling lipid essential in regulating processes involved in sepsis pathophysiology, including endothelial permeability and vascular tone. Serum S1P is progressively reduced in sepsis patients with increasing severity. S1P function depends on binding to its carriers: serum albumin (SA) and high-density lipoproteins (HDL). The aim of this single-center prospective observational study was to determine the contribution of SA- and HDL-associated S1P (SA-S1P and HDL-S1P) to sepsis-induced S1P depletion in plasma with regard to identify future strategies to supplement vasoprotective S1P.
Sequential precipitation of lipoproteins was performed with plasma samples obtained from 100 ICU patients: surgical trauma ( = 20), sepsis ( = 63), and septic shock ( = 17) together with healthy controls ( = 7). Resultant fractions with HDL and SA were analyzed by liquid chromatography coupled to triple-quadrupole mass spectrometry (LC-MS/MS) for their S1P content.
Plasma S1P levels significantly decreased with sepsis severity and showed a strong negative correlation with increased organ failure, quantified by the Sequential Organ Failure Assessment (SOFA) score (rho - 0.59, < 0.001). In controls, total plasma S1P levels were 208 μg/L (187-216 μg/L). In trauma patients, we observed an early loss of SA-S1P (- 70%) with a concurrent increase of HDL-S1P (+ 20%), resulting in unaltered total plasma S1P with 210 μg/L (143-257 μg/L). The decrease of plasma S1P levels with increasing SOFA score in sepsis patients with 180.2 μg/L (123.3-253.0 μg/L) and in septic shock patients with 99.5 μg/L (80.2-127.2 μg/L) was mainly dependent on equivalent reductions of HDL and not SA as carrier protein. Thus, HDL-S1P contributed most to total plasma S1P in patients and progressively dropped with increasing SOFA score.
Reduced plasma S1P was associated with sepsis-induced organ failure. A constant plasma S1P level during the acute phase after surgery was maintained with increased HDL-S1P and decreased SA-S1P, suggesting the redistribution of plasma S1P from SA to HDL. The decrease of plasma S1P levels in patients with increasing sepsis severity was mainly caused by decreasing HDL and HDL-S1P. Therefore, strategies to reconstitute HDL-S1P rather than SA-S1P should be considered for sepsis patients.
1-磷酸鞘氨醇（S1P）是一种信号脂质，在调节脓毒症病理生理学相关过程中至关重要，这些过程包括内皮通透性和血管张力。脓毒症患者血清S1P水平会随着病情加重而逐渐降低。S1P的功能依赖于其与载体的结合：血清白蛋白（SA）和高密度脂蛋白（HDL）。这项单中心前瞻性观察研究的目的是确定与SA和HDL相关的S1P（SA-S1P和HDL-S1P）对脓毒症诱导的血浆S1P消耗的影响，以便确定补充血管保护型S1P的未来策略。
对从100名ICU患者（包括手术创伤患者20例、脓毒症患者63例、感染性休克患者17例）以及健康对照者（7例）获取的血浆样本进行脂蛋白的连续沉淀。通过液相色谱-串联三重四极杆质谱法（LC-MS/MS）分析所得含HDL和SA的组分中的S1P含量。
血浆S1P水平随脓毒症严重程度显著降低，并且与序贯器官衰竭评估（SOFA）评分所量化的器官功能障碍增加呈强烈负相关（rho -0.59，<0.001）。在对照组中，血浆总S1P水平为208μg/L（187 - 216μg/L）。在创伤患者中，我们观察到SA-S1P早期减少（-70%），同时HDL-S1P增加（+20%），导致血浆总S1P不变，为210μg/L（143 - 257μg/L）。脓毒症患者（180.2μg/L，[范围]123.3 - 253.0μg/L）和感染性休克患者（99.5μg/L，[范围]80.2 - 127.2μg/L）中，血浆S1P水平随SOFA评分增加而降低主要依赖于作为载体蛋白的HDL而非SA的等量减少。因此，HDL-S1P在患者血浆总S1P中贡献最大，并随SOFA评分增加而逐渐下降。
血浆S1P降低与脓毒症诱导的器官功能障碍相关。术后急性期血浆S1P水平保持恒定，同时HDL-S1P增加而SA-S1P减少，表示血浆S1P从SA重新分布至HDL。脓毒症严重程度增加患者血浆S1P水平降低主要是由HDL和HDL-S1P减少所致。因此，对于脓毒症患者应考虑采用重建HDL-S1P而非SA-S1P的策略。
