Critical role for integrin-β4 in the attenuation of murine acute lung injury by simvastatin.

Abstract

The statins are a class of 3-hydroxy-3-methylglutaryl-coenzyme A-reductase inhibitors that are recognized to have pleiotropic properties. We previously reported the attenuation of LPS-induced murine acute lung injury (ALI) by simvastatin in vivo and identified relevant effects of simvastatin on endothelial cell (EC) signaling, activation, and barrier function in vitro. In particular, simvastatin induces the upregulation of integrin-β4, which in turn inhibits EC inflammatory responses via attenuation of MAPK signaling. The role of integrin-β4 in murine ALI protection by simvastatin, however, is unknown. We initially confirmed a time- and dose-dependent effect of simvastatin on increased integrin-β4 mRNA expression in human lung EC with peak protein expression evident at 16 h. Subsequently, reciprocal immunoprecipitation demonstrated an attenuation of LPS-induced integrin-β4 tyrosine phosphorylation by simvastatin (5 μM, 16 h). Increased expression of EC inflammatory cytokines [IL-6, IL-8, monocyte chemoattractant protein (MCP)-1, regulated on activation normal T cell expressed and secreted (RANTES)] by LPS (500 ng/ml, 4 h) was also significantly attenuated by simvastatin pretreatment (5 μM, 16 h), but this effect was reversed by cotreatment with an integrin-β4-blocking antibody. Finally, although simvastatin (20 mg/kg) conferred significant protection in murine ALI as evidenced by decreased bronchoalveolar lavage fluid cell counts, protein, inflammatory cytokines (IL-6, IL-1β, MCP-1, RANTES), decreased Evans blue dye albumin extravasation in lung tissue, and changes on lung histology, these effects were reversed by the integrin-β4-blocking antibody (IV, 1 mg/kg, 2 h before LPS). These findings support integrin-β4 as an important mediator of ALI protection by simvastatin and implicate signaling by integrin-β4 as a novel therapeutic target in patients with ALI.

• Authors: Weiguo Chen, Saad Sammani, Sumegha Mitra, Shwu Fan Ma, Joe G N Garcia, Jeffrey R Jacobson
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 303 Issue 4 Pg. L279-85 (Aug 15 2012) ISSN: 1522-1504 [Electronic] United States
• PMID: 22683568 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Ccl2 protein, mouse
• Chemokine CCL2
• Integrin beta4
• Interleukin-6
• Interleukin-8
• Lipopolysaccharides
• Phosphotyrosine
• Simvastatin

Topics

• Acute Lung Injury (drug therapy, pathology, prevention & control)
• Animals
• Chemokine CCL2 (metabolism)
• Endothelial Cells (drug effects, metabolism, pathology)
• Gene Expression Regulation (drug effects)
• Humans
• Inflammation (pathology)
• Integrin beta4 (genetics, metabolism)
• Interleukin-6 (metabolism)
• Interleukin-8 (metabolism)
• Lipopolysaccharides (pharmacology)
• Mice
• Phosphorylation (drug effects)
• Phosphotyrosine (metabolism)
• Simvastatin (pharmacology, therapeutic use)