System biology of multiple organ dysfunction: formation of a ceramide-enriched macro-domain in SIRS/sepsis

Generation of bioactive lipids such as ceramide (Cer) and the formation of Cer-enriched macrodomains are regarded as mediators of SIRS and the development of multiple organ failure. Therefore, we addressed the question of whether there is a difference in the plasma activity of the secreted isoform of the Cer-forming enzyme sphingomyelinase (SMPD1) in patients with various degrees of SIRS/sepsis of different origin as well as in a murine loss of function model. We found plasma activity in critically ill patients (median 262.3 pmol/ml*hour) was significantly higher than age-matched controls (123.6). In patients with fatal outcome, activity increased (+77.4) in comparison with survivors (-252.1). A severity-dependent increase was also analyzed in patients with multiple organ dysfunction syndrome (MODS) following elective cardiac surgery. Beyond immunological detection of increased pSMPD1 in septic patients, we found an increase in Cer-enriched macrodomains in endothelial cells after stimulation with patients' plasma, endotoxin, or TNF.

We also found formation of Cer-enriched macrodomains by immunostaining using specific antibodies directed against Cer, CD14, and Fas. In a loss of function model, we identified 315 transcripts differentially regulated in circulating white blood cells, liver, and lung by use of microarray technology as well as in the cytokine pattern/organ function parameters following polymicrobial cavity infection. Furthermore, host responses in knockout mice were more pronounced with respect to bacterial load in lung, liver, and blood, plasma cytokine levels, thrombocytopenia as well as delayed migration of neutrophils into hepatic tissue.

In conclusion, the results provide demonstration of a biofunctional relevant activity of SMPD1 resulting in altered signal transduction in SIRS, which may contribute to the development of MODS.