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 GN Garcia

Research output: Contribution to journalArticle

192 Citations (Scopus)

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 GN.

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 GN. / 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.
@article{6a4fbf4655334767b9811668ea0e491c,
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 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.",
keywords = "Acute lung injury, Endothelial, Microarrays",
author = "Jacobson, {Jeffrey R.} and Barnard, {Joseph W.} and Grigoryev, {Dmitry N.} and Ma, {Shwu Fan} and Tuder, {Rubin M.} and Garcia, {Joe GN}",
year = "2005",
month = "6",
doi = "10.1152/ajplung.00354.2004",
language = "English (US)",
volume = "288",
journal = "American Journal of Physiology",
issn = "0363-6143",
publisher = "American Physiological Society",
number = "6 32-6",

}

TY - JOUR

T1 - Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury

AU - Jacobson, Jeffrey R.

AU - Barnard, Joseph W.

AU - Grigoryev, Dmitry N.

AU - Ma, Shwu Fan

AU - Tuder, Rubin M.

AU - Garcia, Joe GN

PY - 2005/6

Y1 - 2005/6

N2 - 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.

AB - 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.

KW - Acute lung injury

KW - Endothelial

KW - Microarrays

UR - http://www.scopus.com/inward/record.url?scp=18844394239&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=18844394239&partnerID=8YFLogxK

U2 - 10.1152/ajplung.00354.2004

DO - 10.1152/ajplung.00354.2004

M3 - Article

C2 - 15665042

AN - SCOPUS:18844394239

VL - 288

JO - American Journal of Physiology

JF - American Journal of Physiology

SN - 0363-6143

IS - 6 32-6

ER -