Simvastatin Decreases Lipopolysaccharide-induced Pulmonary Inflammation in Healthy Volunteers

• Published in: American journal of respiratory and critical care medicine 2009-06, Vol.179 (12), p.1107-1114
• Main Authors: Shyamsundar, Murali, McKeown, Scott T. W, O'Kane, Cecilia M, Craig, Thelma R, Brown, Vanessa, Thickett, David R, Matthay, Michael A, Taggart, Clifford C, Backman, Janne T, Elborn, J. Stuart, McAuley, Daniel F
• Format: Article
• Language: English
• Subjects: Acute Lung Injury - chemically induced; Acute Lung Injury - drug therapy; Acute Lung Injury - metabolism; Adult; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; B. Critical Care; Biological and medical sciences; 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; Intensive care medicine; Lipopolysaccharides - adverse effects; Male; Matrix Metalloproteinases - secretion; Medical sciences; Neutrophils - secretion; NF-kappa B - blood; Pneumology; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Reference Values; Simvastatin - administration & dosage; Simvastatin - pharmacokinetics; Simvastatin - therapeutic use; Treatment Outcome
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.200810-1584OC

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. 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. 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. 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). Simvastatin has antiinflammatory effects in the pulmonary and systemic compartment in humans exposed to inhaled LPS.