期刊
THORAX
卷 67, 期 3, 页码 229-237出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/thoraxjnl-2011-200376
关键词
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资金
- Almirall SA, Barcelona, Spain
- CIBERES [CB06/06/0027]
- Regional Government [Prometeo/2008/045, GE-029/10]
- CENIT (Spanish government)
- Almirall (Barcelona, Spain)
- Conselleria de Educacion, Generalitat Valenciana [ACIF/2010/114]
- [SAF2008-03113]
- [SAF2009-08913]
Background Fibroblast to myofibroblast transition is believed to contribute to airway remodelling in lung diseases such as asthma and chronic obstructive pulmonary disease. This study examines the role of aclidinium, a new long-acting muscarinic antagonist, on human fibroblast to myofibroblast transition. Methods Human bronchial fibroblasts were stimulated with carbachol (10(-8) to 10(-5) M) or transforming growth factor-beta 1 (TGF-beta 1; 2 ng/ml) in the presence or absence of aclidinium (10(-9) to 10(-7) M) or different drug modulators for 48 h. Characterisation of myofibroblasts was performed by analysis of collagen type I and a-smooth muscle actin (alpha-SMA) mRNA and protein expression as well as alpha-SMA microfilament immunofluorescence. ERK1/2 phosphorylation, RhoA-GTP and muscarinic receptors (M) 1, 2 and 3 protein expression were determined by western blot analysis and adenosine 3'-5' cyclic monophosphate levels were determined by ELISA. Proliferation and migration of fibroblasts were also assessed. Results Collagen type I and alpha-SMA mRNA and protein expression, as well as percentage alpha-SMA microfilament-positive cells, were upregulated in a similar way by carbachol and TGF-beta 1, and aclidinium reversed these effects. Carbachol-induced myofibroblast transition was mediated by an increase in ERK1/2 phosphorylation, RhoA-GTP activation and cyclic monophosphate downregulation as well as by the autocrine TGF-beta 1 release, which were effectively reduced by aclidinium. TGF-beta 1 activated the non-neuronal cholinergic system. Suppression of M1, M2 or M3 partially prevented carbachol-and TGF-beta 1-induced myofibroblast transition. Aclidinium dose-dependently reduced fibroblast proliferation and migration. Conclusion Aclidinium inhibits human lung fibroblast to myofibrobast transition.
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