Inverse Correlation Between Plasma Sphingosine-1-Phosphate and Ceramide Concentrations in Septic Patients and Their Utility in Predicting Mortality

INTRODUCTION: The aim of this study was to investigate the correlation between plasma sphingosine-1-phosphate (S1P) and ceramide concentrations in sepsis, and the possible mechanisms for altered expression. METHODS: Plasma S1P and ceramide concentrations were measured by HPLC-ESI-MS/MS. HLA-DR (human leukocyte antigen-DR) expression on peripheral blood mononuclear cells was examined by flow cytometry. Platelet sphingosine kinases 1/2 (SphK1/2) mRNA expression, protein content, and enzyme activities were determined by qRT-PCR, western blot, and commercial enzyme assay kits, respectively. RESULTS: Compared with healthy and ICU controls, septic patients had significantly decreased plasma S1P but increased ceramide concentrations (P < 0.05). S1P concentration was negatively associated with the ceramide concentration in the septic patients (r = −0.36, P < 0.05). Linear regression analysis found that plasma S1P and ceramide were linked not only to sequential (sepsis-related) organ failure assessment (SOFA) score but also the HLA-DR expression on circulating monocytes. An receiver operating characteristic analysis, including S1P, ceramide, SOFA score and HLA-DR, showed integrated analysis of S1P and ceramide as the better powerful predictors of septic lethality with area under the curve value of 0.95. More importantly, we found the platelet SphKs activities and the expression levels of SphK1 were significantly decreased in septic patients (P < 0.05). Linear regression analysis revealed platelet SphKs activity was positively associated with the plasma S1P concentration of the septic patients (r = −0.41, P = 0.02). CONCLUSIONS: Integrated analysis of plasma S1P and ceramide predict septic mortality with high accuracy. The decreased platelet SphK1 expression and subsequent reduced SphKs activity might be responsible for the decreased plasma S1P levels during sepsis.