title: 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.affiliation: Center for Translational Respiratory Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. drgarcia@jhmi.edu
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Jacobson
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Barnard
authors.forename: Dmitry N
authors.initials: DN
authors.lastname: Grigoryev
authors.forename: Shwu-Fan
authors.initials: SF
authors.lastname: Ma
authors.forename: Rubin M
authors.initials: RM
authors.lastname: Tuder
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002199:Capillary Permeability / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects; D004731:Endotoxins / Q000633:toxicity; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007249:Inflammation; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000098:blood supply* / Q000276:immunology; D008171:Lung Diseases / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D055370:Lung Injury; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D019821:Simvastatin / Q000494:pharmacology*
chemical_list: D015415:Biomarkers; D004731:Endotoxins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008070:Lipopolysaccharides; D019821:Simvastatin