Acid Sphingomyelinase Promotes Endothelial Stress Response in Systemic Inflammation and Sepsis.

The pathophysiology of sepsis involves activation of acid sphingomyelinase (SMPD1) with subsequent generation of the bioactive mediator ceramide. We herein evaluated the hypothesis that the enzyme exerts biological effects in endothelial stress response. Plasma-secreted sphingomyelinase activity, ceramide generation and lipid raft formation were measured in human microcirculatory endothelial cells (HMEC-1) stimulated with serum obtained from sepsis patients.

Inhibition of sphingomyelin hydrolysis: targeting the lipid mediator ceramide as a key regulator of cellular fate.

Ceramide, an intracellular lipid mediator, is generated by transient hydrolysis of sphingomyelin in response to agonists inducing inflammation and apoptosis, ionizing radiation, chemotherapeutics or ischaemia/reperfusion. An elevated intracellular ceramide production is predominantly induced by an elevated hydrolytic activity of sphingomyelinases or by the activity of enzymes controlling de novo synthesis, such as ceramide synthase. Ceramide is implicated in various cellular responses, acting as an autonomous intracellular effector in cell cycle regulation, differentiation, senescence, and apoptosis.