Simvastatin decreases lipopolysaccharide-induced pulmonary inflammation in healthy volunteers.
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.
Shyamsundar
Murali
M
The Queen's University of Belfast, Grosvenor Road, Belfast, UK. d.f.mcauley@qub.ac.uk
McKeown
Scott T W
ST
O'Kane
Cecilia M
CM
Craig
Thelma R
TR
Brown
Vanessa
V
Thickett
David R
DR
Matthay
Michael A
MA
Taggart
Clifford C
CC
Backman
Janne T
JT
Elborn
J Stuart
JS
McAuley
Daniel F
DF