title: 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.
authors: Dept of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.
authors: Chang Seok
authors: CS
authors: Lee
authors: Eun Hee
authors: EH
authors: Yi
authors: Jin-Ku
authors: JK
authors: Lee
authors: Cheolhee
authors: C
authors: Won
authors: Young Ju
authors: YJ
authors: Lee
authors: Min Kyung
authors: MK
authors: Shin
authors: Young Mok
authors: YM
authors: Yang
authors: Myung-Hee
authors: MH
authors: Chung
authors: Jung Weon
authors: JW
authors: Lee
authors: Sang-Hyun
authors: SH
authors: Sung
authors: Sang-Kyu
authors: SK
authors: Ye
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001980:Bronchi / Q000166:cytology; D045744:Cell Line, Tumor; D018946:Chemokine CCL5 / Q000378:metabolism*; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000166:cytology; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007249:Inflammation; D008168:Lung / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000187:drug effects*; D011014:Pneumonia / Q000139:chemically induced*; D011070:Poly I-C / Q000009:adverse effects*; D034741:RNA, Small Interfering / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D018946:Chemokine CCL5; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D019821:Simvastatin; D004318:Doxycycline; D011070:Poly I-C