Simvastatin delivery via inhalation attenuates airway inflammation in a murine model of asthma.
The dose-response of the pleiotropic effects of statins on airway inflammation has not yet been established and may differ from that of their cholesterol-lowering effects. High oral doses of statins may have adverse effects, and it may be possible to overcome the side effects and low clinical efficacy by administering statins via inhalation. In this study, we hypothesize that simvastatin is a potential anti-inflammatory drug with biological and pharmacokinetic properties suitable for delivery by the inhaled route. Mice were immunized with ovalbumin (OVA) and then challenged with aerosol OVA. Simvastatin was locally delivered by inhalation (i.h.) and intratracheal injection (i.t.) or systematically delivered by intraperitoneal injection (i.p.) and gavage (i.g.) during the OVA challenge. In a mouse model of asthma, i.h. simvastatin significantly and dose-dependently attenuated airway inflammation, remodeling and hyperresponsiveness in a RhoA-dependent pathway. Upon comparing the pharmacodynamics, i.h. simvastatin had a more potent effect than that of i.g. and i.p. simvastatin, and the i.h. or i.t. delivery routes led to a higher drug concentration in local lung tissue and a lower drug concentration in the plasma than that obtained by the i.g. These results suggest that simvastatin is a potential anti-inflammatory drug for airway inflammatory diseases with properties suitable for delivery by inhalation, which will probably reduce the side effects and increase clinical efficacy.
The First People's Hospital of Wujiang City 215200, China.
Lan
L
Xu
Xing-wei
XW
Dong
Liang-liang
LL
Shen
Fen-fen
FF
Li
Jun-xia
JX
Jiang
Rui
R
Cao
Hong-yi
HY
Yao
Hui-juan
HJ
Shen
Yun
Y
Sun
Qiang-min
QM
Xie
D000280:Administration, Inhalation; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy* / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002452:Cell Count; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism; D019821:Simvastatin / Q000008:administration & dosage*
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012333:RNA, Messenger; D010047:Ovalbumin; D019821:Simvastatin