Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury

Jeffrey R. Jacobson, Joseph W. Barnard, Dmitry N. Grigoryev, Shwu Fan Ma, Rubin M. Tuder, Joe G.N. Garcia

Research output: Contribution to journalArticle

202 Scopus citations

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 ALL 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.

Original languageEnglish (US)
Pages (from-to)L1026-L1032
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume288
Issue number6 32-6
DOIs
StatePublished - Jun 1 2005
Externally publishedYes

Keywords

  • Acute lung injury
  • Endothelial
  • Microarrays

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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