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


OBJECTIVE
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.


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.
Zeki
Amir A
AA
Center for Comparative Respiratory Biology and Medicine, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of California Davis, Davis, California 95616, USA.
Franzi
Lisa
L
Last
Jerold
J
Kenyon
Nicholas J
NJ
D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000276:immunology*; D053898:Biosynthetic Pathways / Q000187:drug effects*; D016535:Bronchial Hyperreactivity / Q000188:drug therapy / Q000276:immunology*; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007249:Inflammation / Q000517:prevention & control; D008798:Mevalonic Acid / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D019821:Simvastatin / Q000494:pharmacology*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; D008798:Mevalonic Acid