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 mu g/ 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; similar to 35 - 60% reduction). Simvastatin also decreased BAL albumin (similar to 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-kappa B 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.