Role of increased sphingomyelinase activity in apoptosis and organ failure of patients with severe sepsis.
Numerous studies support the notion that an activation of sphingomyelinases and a subsequent increase of the concentration of the bioactive lipid mediator ceramide are critical in the concert of inflammatory stimuli and to the induction of apoptosis during inflammation. Here we show that patients with severe sepsis exhibit an enhanced sphingolytic activity in comparison with controls [262 pmol/(mlxh) vs. 123.6 pmol/(mlxh), P<0.005]. During the clinical course, a further increase was paralleled by the severity of illness and by fatal outcome. Moreover, we show that oxidative stress may partially account for the increased activity through posttranslational modification of the enzyme. In a murine endotoxic shock model, administration of a low molecular weight inhibitor diminished the rise in enzymatic activity and improved the survival rate. In liver specimen, inhibition of activity correlated with a reduced rate of hepato-cellular apoptosis. Our data support the concept that activation of the plasmatic isoform of sphingomyelinase may play a critical role in the development of apoptosis and organ failure in sepsis. An inhibition of the secreted isoform of sphingomyelinase should be explored further as a potential target in the complicated puzzle of sepsis.
Claus
Ralf A
RA
Department of Anaesthesiology and Intensive Care Medicine, Friedrich Schiller University Jena, Jena, Germany. ralf.claus@med.uni-jena.de
Bunck
Alexander C
AC
Bockmeyer
Clemens L
CL
Brunkhorst
Frank M
FM
Lösche
Wolfgang
W
Kinscherf
Ralf
R
Deigner
Hans-Peter
HP
D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D001205:Ascorbic Acid / Q000737:chemistry; D001774:Blood Chemical Analysis; D002518:Ceramides / Q000378:metabolism; D003891:Desipramine / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007249:Inflammation; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008875:Middle Aged; D015233:Models, Statistical; D018384:Oxidative Stress; D018805:Sepsis / Q000473:pathology*; D012772:Shock, Septic / Q000473:pathology; D013108:Sphingomyelin Phosphodiesterase / Q000096:biosynthesis* / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome
D002518:Ceramides; D004731:Endotoxins; D008055:Lipids; D013108:Sphingomyelin Phosphodiesterase; D001205:Ascorbic Acid; D003891:Desipramine