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Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury

Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury Therapies to limit the life-threatening vascular leak observed in patients with acute lung injury (ALI) are currently lacking. We explored the effect of simvastatin, a 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor that mediates endothelial cell barrier protection in vitro, in a murine inflammatory model of ALI. C57BL/6J mice were treated with simvastatin (5 or 20 mg/kg body wt via intraperitoneal injection) 24 h before and again concomitantly with intratracheally administered LPS (2 µg/g body wt). Inflammatory indexes bronchoalveolar lavage (BAL) myeloperoxidase activity and total neutrophil counts assessed at 24 h with histological confirmation were markedly increased after LPS alone but significantly reduced in mice that also received simvastatin (20 mg/kg; ∼35–60% reduction). Simvastatin also decreased BAL albumin (∼50% reduction) and Evans blue albumin dye extravasation into lung tissue (100%) consistent with barrier protection. Finally, the sustained nature of simvastatin-mediated lung protection was assessed by analysis of simvastatin-induced gene expression (Affymetrix platform). LPS-mediated lung gene expression was significantly modulated by simvastatin within a number of gene ontologies (e.g., inflammation and immune response, NF-κB regulation) and with respect to individual genes implicated in the development or severity of ALI (e.g., IL-6, Toll-like receptor 4). Together, these findings confirm significant protection by simvastatin on LPS-induced lung vascular leak and inflammation and implicate a potential role for statins in the management of ALI. acute lung injury; endothelial; microarrays Address for reprint requests and other correspondence: Joe G. N. Garcia, Division of Pulmonary and Critical Care Medicine, Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224 (E-mail: drgarcia@jhmi.edu ) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png AJP - Lung Cellular and Molecular Physiology The American Physiological Society

Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury

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References (43)

Publisher
The American Physiological Society
Copyright
Copyright © 2011 the American Physiological Society
ISSN
1040-0605
eISSN
1522-1504
DOI
10.1152/ajplung.00354.2004
pmid
15665042
Publisher site
See Article on Publisher Site

Abstract

Therapies to limit the life-threatening vascular leak observed in patients with acute lung injury (ALI) are currently lacking. We explored the effect of simvastatin, a 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor that mediates endothelial cell barrier protection in vitro, in a murine inflammatory model of ALI. C57BL/6J mice were treated with simvastatin (5 or 20 mg/kg body wt via intraperitoneal injection) 24 h before and again concomitantly with intratracheally administered LPS (2 µg/g body wt). Inflammatory indexes bronchoalveolar lavage (BAL) myeloperoxidase activity and total neutrophil counts assessed at 24 h with histological confirmation were markedly increased after LPS alone but significantly reduced in mice that also received simvastatin (20 mg/kg; ∼35–60% reduction). Simvastatin also decreased BAL albumin (∼50% reduction) and Evans blue albumin dye extravasation into lung tissue (100%) consistent with barrier protection. Finally, the sustained nature of simvastatin-mediated lung protection was assessed by analysis of simvastatin-induced gene expression (Affymetrix platform). LPS-mediated lung gene expression was significantly modulated by simvastatin within a number of gene ontologies (e.g., inflammation and immune response, NF-κB regulation) and with respect to individual genes implicated in the development or severity of ALI (e.g., IL-6, Toll-like receptor 4). Together, these findings confirm significant protection by simvastatin on LPS-induced lung vascular leak and inflammation and implicate a potential role for statins in the management of ALI. acute lung injury; endothelial; microarrays Address for reprint requests and other correspondence: Joe G. N. Garcia, Division of Pulmonary and Critical Care Medicine, Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224 (E-mail: drgarcia@jhmi.edu )

Journal

AJP - Lung Cellular and Molecular PhysiologyThe American Physiological Society

Published: Jun 1, 2005

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