Simvastatin decreases lipopolysaccharide-induced pulmonary inflammation in healthy volunteers

M Shyamsundar, ST McKeown, CM O'Kane, TR Craig, V Brown, David Thickett, MA Matthay, CC Taggart, JT Backman, JS Elborn, DF McAuley

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190 Citations (Scopus)


RATIONALE: 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. OBJECTIVES: 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. MEASUREMENTS AND MAIN 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.
Original languageEnglish
Pages (from-to)1107-14
Number of pages8
JournalAmerican Journal of Respiratory and Critical Care Medicine
Issue number12
Publication statusPublished - 15 Jun 2009


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