Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury.

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 microg/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; approximately 35-60% reduction). Simvastatin also decreased BAL albumin (approximately 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-kappaB 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.

• Authors: Jeffrey R Jacobson, Joseph W Barnard, Dmitry N Grigoryev, Shwu-Fan Ma, Rubin M Tuder, Joe G N Garcia
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 288 Issue 6 Pg. L1026-32 (Jun 2005) ISSN: 1040-0605 [Print] United States
• PMID: 15665042 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Biomarkers
• Endotoxins
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Lipopolysaccharides
• Simvastatin

Topics

• Animals
• Biomarkers (metabolism)
• Bronchoalveolar Lavage Fluid (cytology)
• Capillary Permeability (drug effects)
• Endothelial Cells (drug effects)
• Endotoxins (toxicity)
• Gene Expression Profiling
• Gene Expression Regulation (drug effects)
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Inflammation
• Lipopolysaccharides (pharmacology)
• Lung (blood supply, immunology)
• Lung Diseases (chemically induced, immunology, prevention & control)
• Lung Injury
• Male
• Mice
• Mice, Inbred C57BL
• Oligonucleotide Array Sequence Analysis
• Simvastatin (pharmacology)