Simvastatin attenuates experimental small airway remodelling in rats.
OBJECTIVE
The aim of this study was to assess the beneficial effects of simvastatin on cigarette smoke-induced small airway remodeling in rats.


METHODS
Simvastatin was administered at different doses for 16 weeks to rats with cigarette smoke-induced small airway remodelling. Morphological analyses were performed, and collagen deposition, production of growth factors, inflammatory parameters and RhoA, as well as the Smad signalling pathway in the lungs, were examined.


RESULTS
Simvastatin attenuated small airway wall thickening and prevented the increase in lung hydroxyproline content and collagen deposition induced in airway walls by cigarette smoking. In addition, simvastatin downregulated transforming growth factor-beta1 and connective tissue growth factor protein and gene expression in the lungs. Furthermore, accumulation of macrophages and neutrophils and increases in tumour necrosis factor-alpha concentration in BAL fluid were inhibited by simvastatin. Simultaneously, the expression of RhoA and the phosphorylation of Smad2 and Smad3 in lungs exposed to cigarette smoke were inhibited during simvastatin administration. However, the increased expression of Smad2 and Smad3 proteins and the decreased level of Smad7 protein in remodelled lungs were not affected by simvastatin.


CONCLUSIONS
Simvastatin attenuated experimental small airway remodelling, as indicated by decreases in collagen deposition and small airway wall thickening. Simvastatin may inhibit cigarette smoke-induced small airway remodelling by reducing growth factor expression and inflammation. The mechanism of action of simvastatin on small airway remodelling involved RhoA and the Smad signalling pathway. These findings indicate that simvastatin may have potential beneficial effects in the treatment of COPD.
Ou
Xue-Mei
XM
Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
Wen
Fu-Qiang
FQ
Uhal
Bruce D
BD
Feng
Yu-Lin
YL
Huang
Xiang-Yang
XY
Wang
Tao
T
Wang
Ke
K
Liu
Dai-Shun
DS
Wang
Xun
X
Chen
Lei
L
D056151:Airway Remodeling / Q000187:drug effects*; D000818:Animals; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006909:Hydroxyproline / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D019821:Simvastatin / Q000494:pharmacology*; D051785:Smad Proteins / Q000378:metabolism; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D051785:Smad Proteins; D014028:Tobacco Smoke Pollution; D053773:Transforming Growth Factor beta1; D003094:Collagen; D019821:Simvastatin; D020742:rhoA GTP-Binding Protein; D006909:Hydroxyproline