title: Simvastatin decreases lipopolysaccharide-induced pulmonary inflammation in healthy volunteers.
abstract: BACKGROUND
  Simvastatin inhibits inflammatory responses in vitro and in murine models of lung inflammation in vivo. As simvastatin modulates a number of the underlying processes described in acute lung injury (ALI), it may be a potential therapeutic option.
  
  
  OBJECTIVE
  To investigate in vivo if simvastatin modulates mechanisms important in the development of ALI in a model of acute lung inflammation induced by inhalation of lipopolysaccharide (LPS) in healthy human volunteers.
  
  
  METHODS
  Thirty healthy subjects were enrolled in a double-blind, placebo-controlled study. Subjects were randomized to receive 40 mg or 80 mg of simvastatin or placebo (n = 10/group) for 4 days before inhalation of 50 microg LPS. Measurements were performed in bronchoalveolar lavage fluid (BALF) obtained at 6 hours and plasma obtained at 24 hours after LPS challenge. Nuclear translocation of nuclear factor-kappaB (NF-kappaB) was measured in monocyte-derived macrophages.
  
  
  RESULTS
  Pretreatment with simvastatin reduced LPS-induced BALF neutrophilia, myeloperoxidase, tumor necrosis factor-alpha, matrix metalloproteinases 7, 8, and 9, and C-reactive protein (CRP) as well as plasma CRP (all P < 0.05 vs. placebo). There was no significant difference between simvastatin 40 mg and 80 mg. BALF from subjects post-LPS inhalation induced a threefold up-regulation in nuclear NF-kappaB in monocyte-derived macrophages (P < 0.001); pretreatment with simvastatin reduced this by 35% (P < 0.001).
  
  
  CONCLUSIONS
  Simvastatin has antiinflammatory effects in the pulmonary and systemic compartment in humans exposed to inhaled LPS.
authors.affiliation: The Queen's University of Belfast, Grosvenor Road, Belfast, UK. d.f.mcauley@qub.ac.uk
authors.forename: Murali
authors.initials: M
authors.lastname: Shyamsundar
authors.forename: Scott T W
authors.initials: ST
authors.lastname: McKeown
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: O'Kane
authors.forename: Thelma R
authors.initials: TR
authors.lastname: Craig
authors.forename: Vanessa
authors.initials: V
authors.lastname: Brown
authors.forename: David R
authors.initials: DR
authors.lastname: Thickett
authors.forename: Michael A
authors.initials: MA
authors.lastname: Matthay
authors.forename: Clifford C
authors.initials: CC
authors.lastname: Taggart
authors.forename: Janne T
authors.initials: JT
authors.lastname: Backman
authors.forename: J Stuart
authors.initials: JS
authors.lastname: Elborn
authors.forename: Daniel F
authors.initials: DF
authors.lastname: McAuley