Simvastatin inhibits inflammatory properties of Staphylococcus aureus alpha-toxin.
BACKGROUND
Simvastatin, a 3-hydroxy-methylglutaryl coenzyme A reductase inhibitor, has been shown to lower serum cholesterol levels in clinical use. Moreover, statins exert beneficial effects in vascular diseases by inhibition of leukocyte rolling, adherence, and transmigration. The aim of this study was to determine if pretreatment with simvastatin attenuates Staphylococcus aureus alpha-toxin-induced increase in leukocyte-endothelial interactions during exotoxemia.


RESULTS
The effects of simvastatin on leukocyte-endothelial cell interactions were observed by intravital microscopy in the rat mesenteric microcirculation. Simvastatin (50 or 100 microg/kg) was administered 18 hours before the study. Activation of microcirculation was induced by bolus administration of 40 microg/kg S aureus alpha-toxin. Exotoxemia resulted in a significant and time-dependent increase in leukocyte rolling, adherence, and transmigration of leukocytes as well as P-selectin expression on the intestinal vascular endothelium. Pretreatment with simvastatin significantly inhibited exotoxin-induced leukocyte rolling from 71+/-10 to 14+/-4.7 cells/min (P<0.01) and adherence from 14+/-3.5 to 0.4+/-0.2 cells (P<0.01). In addition, simvastatin pretreatment significantly inhibited transmigration of leukocytes from 10.5+/-1.2 to 4.2+/-0.9 (P<0.05) cells. Immunohistochemical detection of endothelial cell adhesion molecule P-selectin showed a 50% decrease in endothelial cell surface expression after simvastatin treatment. Furthermore, simvastatin treatment resulted in enhanced expression of endothelial cell NO synthase III in the intestinal microcirculation.


CONCLUSIONS
These results demonstrate that simvastatin interferes with exotoxin-induced leukocyte-endothelial cell interactions, which may be relevant in various infectious diseases. Statin treatment may offer a new therapeutic strategy for these clinical conditions.
Pruefer
Diethard
D
Department of Cardiothoracic and Vascular, Johannes Gutenberg-University, Mainz, Germany.
Makowski
Joachim
J
Schnell
Martin
M
Buerke
Ute
U
Dahm
Manfred
M
Oelert
Hellmut
H
Sibelius
Ulf
U
Grandel
Ulrich
U
Grimminger
Friedrich
F
Seeger
Werner
W
Meyer
Jürgen
J
Darius
Harald
H
Buerke
Michael
M
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D046508:Culture Techniques; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D006439:Hemodynamics; D006460:Hemolysin Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology; D008297:Male; D008642:Mesenteric Veins / Q000033:anatomy & histology / Q000187:drug effects / Q000503:physiopathology; D018715:Microscopy, Video; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000276:immunology; D052250:Nitric Oxide Synthase Type III; D019007:P-Selectin / Q000032:analysis / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology*; D013203:Staphylococcal Infections / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D014115:Toxemia / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D014699:Venules / Q000187:drug effects / Q000503:physiopathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001427:Bacterial Toxins; D006460:Hemolysin Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019007:P-Selectin; C021091:staphylococcal alpha-toxin; D019821:Simvastatin; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat