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Simvastatin Decreases Lipopolysaccharide-induced Pulmonary Inflammation in Healthy Volunteers

¹ Respiratory Medicine Research Programme, Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University of Belfast, Belfast, United Kingdom; ² Lung Injury and Fibrosis Treatment Programme, Department of Medical Sciences, Medical School, University of Birmingham, Birmingham, United Kingdom; ³ Cardiovascular Research Institute, University of California, San Francisco, California; and ⁴ Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

Correspondence and requests for reprints should be addressed to Danny McAuley, M.D., F.R.C.P., Microbiology Building, The Queen's University of Belfast, Grosvenor Road, Belfast BT12 6BN, UK. E-mail: d.f.mcauley{at}qub.ac.uk

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 µg 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-B (NF-B) was measured in monocyte-derived macrophages.

Measurements and Main Results: Pretreatment with simvastatin reduced LPS-induced BALF neutrophilia, myeloperoxidase, tumor necrosis factor-, 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-B 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.

Clinical trial registered with www.controlled-trials.com (ISRCTN21056528).

Key Words: cytokines • matrix metalloproteinases • endotoxin • nuclear factor-B • simvastatin • acute lung injury

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Pharmacologic therapies have not proven to be effective for acute lung injury (ALI). Experimental data suggest simvastatin has potential as a treatment for ALI. It is unknown if simvastatin reduces pulmonary inflammation in vivo in humans. What This Study Adds to the Field Simvastatin pretreatment has antiinflammatory effects in the pulmonary compartment in a model of ALI induced by inhaled lipopolysaccharide in humans.

 

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				M. B. Fessler Simvastatin as a Potential Therapeutic for Acute Respiratory Distress Syndrome Am. J. Respir. Crit. Care Med., November 15, 2009; 180(10): 1031 - 1031. [Full Text] [PDF]

				M. Shyamsundar, C. M. O'Kane, and D. F. McAuley Simvastatin as a Potential Therapeutic for Acute Respiratory Distress Syndrome Am. J. Respir. Crit. Care Med., November 15, 2009; 180(10): 1031 - 1032. [Full Text] [PDF]