Loss of sphingosine 1-phosphate (S1P) in septic shock is predominantly caused by decreased levels of high-density lipoproteins (HDL)

Background: 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.

Methods: Sequential precipitation of lipoproteins was performed with plasma samples obtained from 100 ICU patients: surgical trauma (n = 20), sepsis (n = 63), and septic shock (n = 17) together with healthy controls (n = 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.

Results: 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, P < 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.

Conclusions: 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.