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Simvastatin inhibits airway hyperreactivity: implications for the mevalonate pathway and beyond.

AbstractRATIONALE:
Statin use has been linked to improved lung health in asthma and chronic obstructive pulmonary disease. We hypothesize that statins inhibit allergic airway inflammation and reduce airway hyperreactivity via a mevalonate-dependent mechanism.
OBJECTIVES:
To determine whether simvastatin attenuates airway inflammation and improves lung physiology by mevalonate pathway inhibition.
METHODS:
BALB/c mice were sensitized to ovalbumin over 4 weeks and exposed to 1% ovalbumin aerosol over 2 weeks. Simvastatin (40 mg/kg) or simvastatin plus mevalonate (20 mg/kg) was injected intraperitoneally before each ovalbumin exposure.
MEASUREMENTS AND MAIN RESULTS:
Simvastatin reduced total lung lavage leukocytes, eosinophils, and macrophages (P < 0.05) in the ovalbumin-exposed mice. Cotreatment with mevalonate, in addition to simvastatin, reversed the antiinflammatory effects seen with simvastatin alone (P < 0.05). Lung lavage IL-4, IL-13, and tumor necrosis factor-alpha levels were all reduced by treatment with simvastatin (P < 0.05). Simvastatin treatment before methacholine bronchial challenge increased lung compliance and reduced airway hyperreactivity (P = 0.0001).
CONCLUSIONS:
Simvastatin attenuates allergic airway inflammation, inhibits key helper T cell type 1 and 2 chemokines, and improves lung physiology in a mouse model of asthma. The mevalonate pathway appears to modulate allergic airway inflammation, while the beneficial effects of simvastatin on lung compliance and airway hyperreactivity may be independent of the mevalonate pathway. Simvastatin and similar agents that modulate the mevalonate pathway may prove to be treatments for inflammatory airway diseases, such as asthma.
AuthorsAmir A Zeki, Lisa Franzi, Jerold Last, Nicholas J Kenyon
JournalAmerican journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 180 Issue 8 Pg. 731-40 (Oct 15 2009) ISSN: 1535-4970 [Electronic] United States
PMID19608720 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Simvastatin
  • Mevalonic Acid
Topics
  • Animals
  • Asthma (drug therapy, immunology)
  • Biosynthetic Pathways (drug effects)
  • Bronchial Hyperreactivity (drug therapy, immunology)
  • Bronchial Provocation Tests
  • Bronchoalveolar Lavage Fluid (cytology)
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
  • Inflammation (prevention & control)
  • Mevalonic Acid (immunology, metabolism)
  • Mice
  • Mice, Inbred BALB C
  • Simvastatin (pharmacology)

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