Simvastatin Decreases Lipopolysaccharide-induced Pulmonary Inflammation in Healthy Volunteers

Murali Shyamsundar, Scott McKeown, Cecilia O'Kane, Thelma Craig, Vanessa Brown, D.R. Thickett, M.A. Matthay, Clifford Taggart, J.T. Backman, Joseph Elborn, Danny McAuley

Research output: Contribution to journalArticlepeer-review

192 Citations (Scopus)

Abstract

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)1107-1114
Number of pages8
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume179
Issue number12
Early online date26 Mar 2009
DOIs
Publication statusPublished - 15 Jun 2009

Keywords

  • cytokines
  • matrix metalloproteinases
  • endotoxin
  • nuclear factor-kB
  • simvastatin
  • acute lung injury

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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