title: Simvastatin abrogates inflamed neutrophil adhesive properties, in association with the inhibition of Mac-1 integrin expression and modulation of Rho kinase activity.
abstract: OBJECTIVE
  Leukocytes play a primary role in vascular inflammation, and thus an understanding of the pathways involved in the activation of these cells and means to inhibit their consequent adhesion to the vessel wall is of significant interest. This study aimed to determine whether statins have a direct effect upon neutrophil adhesive properties under inflammatory conditions.
  
  
  METHODS
  Neutrophils from healthy individuals were subjected to adhesion assays (with fibronectin as ligand) and flow cytometry.
  
  
  RESULTS
  In the presence of a TNF-α inflammatory stimulus, neutrophils displayed a rapid and substantial enhancement in their adhesive properties that was abrogated by preincubation of cells with simvastatin. Neutrophil surface expression of the Mac-1 integrin subunit, CD11b, was augmented by TNF-α, and this increased expression was also inhibited by simvastatin. TNF-α also induced neutrophil LFA-1 and Mac-1 activation, but this activation was not blocked by simvastatin. Interestingly, while addition of the isoprenoids, geranygerayl pyrophosphate and farnesyl pyrophosphate, to cells did not alter the effect of simvastatin on TNF-α-stimulated adhesion, concurrent incubation of cells with the Rho kinase (ROCK) inhibitor reversed the effects of simvastatin on neutrophil adhesion and CD11b expression.
  
  
  CONCLUSIONS
  Simvastatin appears to have direct anti-inflammatory effects in neutrophils that may be mediated by modulation of ROCK activity.
authors.affiliation: INCT de Sangue, Hematology and Hemotherapy Center, School of Medicine, University of Campinas-UNICAMP, Campinas, Sao Paulo, Brazil.
authors.forename: Angélica Aparecida Antoniellis
authors.initials: AA
authors.lastname: Silveira
authors.forename: Venina Marcela
authors.initials: VM
authors.lastname: Dominical
authors.forename: Mariana
authors.initials: M
authors.lastname: Lazarini
authors.forename: Fernando Ferreira
authors.initials: FF
authors.lastname: Costa
authors.forename: Nicola
authors.initials: N
authors.lastname: Conran
mesh_terms: D000293:Adolescent; D000328:Adult; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000276:immunology; D002478:Cells, Cultured; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D016177:Macrophage-1 Antigen / Q000276:immunology*; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D019821:Simvastatin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D055815:Young Adult
chemical_list: D015815:Cell Adhesion Molecules; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016177:Macrophage-1 Antigen; D014409:Tumor Necrosis Factor-alpha; D019821:Simvastatin