Simvastatin decreases lipopolysaccharide-induced pulmonary inflammation in healthy volunteers

Am J Respir Crit Care Med. 2009 Jun 15;179(12):1107-14. doi: 10.1164/rccm.200810-1584OC. Epub 2009 Mar 26.


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.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury / chemically induced
  • Acute Lung Injury / drug therapy*
  • Acute Lung Injury / metabolism
  • Adult
  • Bronchoalveolar Lavage Fluid / chemistry
  • Cytokines / metabolism
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Enzyme-Linked Immunosorbent Assay
  • Escherichia coli*
  • Female
  • Flow Cytometry
  • Follow-Up Studies
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / administration & dosage
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacokinetics
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use*
  • Lipopolysaccharides / adverse effects*
  • Male
  • Matrix Metalloproteinases / metabolism
  • NF-kappa B / blood
  • Neutrophils / metabolism
  • Reference Values
  • Simvastatin / administration & dosage
  • Simvastatin / pharmacokinetics
  • Simvastatin / therapeutic use*
  • Treatment Outcome


  • Cytokines
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Lipopolysaccharides
  • NF-kappa B
  • Simvastatin
  • Matrix Metalloproteinases

Associated data

  • ISRCTN/ISRCTN21056528