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1 Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA
2 Department of Pathology, Johns Hopkins University, Baltimore, MD, USA
* To whom correspondence should be addressed. E-mail: drgarcia{at}jhmi.edu.
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, an 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 weight via intraperitoneal injection) 24 h prior to and again concomitant with intratracheally-administered LPS (2 µg/g body weight). Inflammatory indices (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
(EBA) 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
B regulation) and with respect to individual genes implicated in the development or severity of ALI (e.g. IL-6, TLR4). Together, these findings confirm significant protection by simvastatin on LPSinduced lung vascular leak and inflammation and implicate a potential role for statins in the management of ALI.
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