Simvastatin suppresses RANTES-mediated neutrophilia in polyinosinic–polycytidylic acid-induced pneumonia

Abstract

Recently, statins have been shown to have anti-inflammatory effects on lung inflammatory diseases. However, the mechanisms of action of simvastatin in viral pneumonia have yet to be elucidated, although viral infection remains a considerable health threat. In this study, we hypothesised that simvastatin inhibits polyinosinic-polycytidylic acid (poly I:C)-induced airway inflammation, such as RANTES (regulated on activation, normal T-cell expressed and secreted) expression and inflammatory cell recruitment.In bronchial cells, the effect of simvastatin on poly I:C-induced RANTES expression and signal transducer and activator of transcription (STAT)3-mediated signal transduction was determined using an ELISA and short hairpin (sh)RNA system. In a poly I:C-induced pneumonia mouse model, immunological changes in the lungs after simvastatin inhalation, such as inflammatory cell recruitment and cytokine/chemokine release, were examined.In poly I:C-stimulated bronchial cells, RANTES secretion was increased by STAT3 activation, and simvastatin suppressed poly I:C-induced STAT3 activation, resulting in inhibition of RANTES expression. In BALB/c mice stimulated with inhaled poly I:C, RANTES expression and neutrophil infiltration into the airway were elevated. However, simvastatin treatment attenuated STAT3 activation, RANTES release and subsequent neutrophilia in the lungs.These findings suggest that simvastatin inhibits airway inflammation, but there are other mechanisms that need to be fully elucidated.

Simvastatin-induced effects on bronchial epithelial cells from COPD donors

“…I read with interest the report by LEE et al [1] on inhibition by simvastatin of double-stranded (ds)RNA-induced bronchial epithelial cell production of RANTES, with supportive in vivo data in mice. dsRNA is an interesting challenge agent.…”

“…However, in general, the concentrations of simvastatin which are anti-inflammatory in vitro ( [1,4] and references cited therein) are approximately 20-times larger than the therapeutic blood levels [4]. This fact casts doubt on the direct clinical relevance of the in vitro cell data, except for the tentative use of very large statin doses in terminally ill individuals.…”

“…dsRNA is an interesting challenge agent. It not only mimics viral infection, as noted by LEE et al [1], but may also reflect effects of released mRNA or secondary structure from necrotic cells that commonly occur in severe bronchial diseases (for references, see [2]). RANTES, similar to interferon (IFN)-b, is induced by activation of the transcription factor IRF3 (IFN regulatory factor 3) [3].…”

“…RANTES, similar to interferon (IFN)-b, is induced by activation of the transcription factor IRF3 (IFN regulatory factor 3) [3]. Hence, the anti-RANTES effect demonstrated by LEE et al [1] may agree with our current demonstration of simvastatin-induced inhibition of IRF3 phosphorylation in dsRNA-challenged bronchial epithelial cells; we used primary cells obtained by bronchial brushings in chronic obstructive pulmonary disease (COPD) patients [4]. We further showed that the inhibition of IRF3 activation occurred without effects on nuclear factor (NF)-kB.…”

“…This fact casts doubt on the direct clinical relevance of the in vitro cell data, except for the tentative use of very large statin doses in terminally ill individuals. LEE et al [1] successfully used the purely experimental, topical airway route for simvastatin administration to mice in vivo. However, they did not discuss the concentration issue; indeed, it is rarely discussed in current literature [4].…”