Journal
RESPIROLOGY
Volume 14, Issue 5, Pages 734-745Publisher
WILEY
DOI: 10.1111/j.1440-1843.2009.01549.x
Keywords
cigarette smoke; connective simvastatin; small airway remodelling; tissue growth factor; transforming growth factor-beta(1)
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Funding
- National Natural Science Foundation of China [30425007, 30370627, 30670921]
- Specialized Research Fund for the Doctoral Program of Higher Education of China [20060610064]
- China Medical Board of New York [00-722, 06-834]
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Background and 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-beta(1) 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.
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