title: Simvastatin inhibits inflammatory properties of Staphylococcus aureus alpha-toxin.
abstract: 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.
authors.affiliation: Department of Cardiothoracic and Vascular, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Diethard
authors.initials: D
authors.lastname: Pruefer
authors.forename: Joachim
authors.initials: J
authors.lastname: Makowski
authors.forename: Martin
authors.initials: M
authors.lastname: Schnell
authors.forename: Ute
authors.initials: U
authors.lastname: Buerke
authors.forename: Manfred
authors.initials: M
authors.lastname: Dahm
authors.forename: Hellmut
authors.initials: H
authors.lastname: Oelert
authors.forename: Ulf
authors.initials: U
authors.lastname: Sibelius
authors.forename: Ulrich
authors.initials: U
authors.lastname: Grandel
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Jürgen
authors.initials: J
authors.lastname: Meyer
authors.forename: Harald
authors.initials: H
authors.lastname: Darius
authors.forename: Michael
authors.initials: M
authors.lastname: Buerke
mesh_terms: 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
chemical_list: 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