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

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)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume288
Issue number6 32-6
DOIs
StatePublished - Jun 2005
Externally publishedYes

Fingerprint

Simvastatin
Lung Injury
Blood Vessels
Inflammation
Acute Lung Injury
Lung
Bronchoalveolar Lavage
Albumins
Hydroxymethylglutaryl CoA Reductases
Gene Expression
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Evans Blue
Gene Ontology
Toll-Like Receptor 4
Cytoprotection
Intraperitoneal Injections
Inbred C57BL Mouse
Peroxidase
Interleukin-6
Neutrophils

Keywords

  • Acute lung injury
  • Endothelial
  • Microarrays

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Cell Biology
  • Physiology

Cite this

Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury. / Jacobson, Jeffrey R.; Barnard, Joseph W.; Grigoryev, Dmitry N.; Ma, Shwu Fan; Tuder, Rubin M.; Garcia, Joe G N.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 288, No. 6 32-6, 06.2005.

Research output: Contribution to journalArticle

Jacobson, Jeffrey R. ; Barnard, Joseph W. ; Grigoryev, Dmitry N. ; Ma, Shwu Fan ; Tuder, Rubin M. ; Garcia, Joe G N. / Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2005 ; Vol. 288, No. 6 32-6.
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