Statin treatment after onset of sepsis in a murine model improves survival.
BACKGROUND
HMG-CoA-reductase inhibitors have been shown to exhibit pronounced immunomodulatory effects independent of lipid lowering. We have recently demonstrated that pretreatment with simvastatin profoundly improves survival in a cecal ligation and perforation (CLP) model of sepsis. Here, we studied whether treatment with simvastatin after onset of sepsis-induced hemodynamic alterations is beneficial and whether prolonged survival can also be achieved with other statins.


RESULTS
Mice were rendered septic by CLP. At 6 hours after sepsis induction, when profound hemodynamic alterations were manifest, treatment with atorvastatin, fluvastatin, pravastatin, simvastatin, or placebo was initiated. Except for fluvastatin (27+/-2.3 hours), survival time was extended from 23+/-1.2 hours for placebo-treated mice to 37+/-3.6 hours for simvastatin-treated, to 40+/-4.2 hours for atorvastatin-treated, and to 39+/-3.9 hours for pravastatin-treated mice. This profound improvement is based on the preservation of cardiac function and hemodynamic status in statin-treated animals, both of which are severely impaired in untreated CLP mice. As underlying mechanisms, improved susceptibility to endothelial nitric oxide synthase stimulation and reduced endothelial adhesion of leukocytes could be demonstrated after statin treatment.


CONCLUSIONS
Well established in the treatment of lipid disorders and coronary artery disease, statins harbor the additional and novel potential of effective sepsis treatment. This benefit extends to several but not all statins tested.
Medizinische Klinik I, RWTH Aachen, 52057 Aachen, Germany. mmerx@ukaachen.de
Marc W
MW
Merx
Elisa A
EA
Liehn
Jürgen
J
Graf
Annette
A
van de Sandt
Maren
M
Schaltenbrand
Jürgen
J
Schrader
Peter
P
Hanrath
Christian
C
Weber
D000818:Animals; D002302:Cardiac Output; D002448:Cell Adhesion; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004452:Echocardiography; D004730:Endothelium, Vascular / Q000166:cytology; D006439:Hemodynamics / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D007962:Leukocytes / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D015996:Survival Rate
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D052250:Nitric Oxide Synthase Type III