Aclidinium inhibits human lung fibroblast to myofibroblast transition.
Aclidinium inhibits human lung fibroblast to myofibroblast transition.
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DOI：
10.1136/thoraxjnl-2011-200376
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发表时间：
2012-03
期刊：
影响因子：
10
通讯作者：
Cortijo J
中科院分区：
文献类型：
--
作者：
Milara J;Serrano A;Peiró T;Gavaldà A;Miralpeix M;Morcillo EJ;Cortijo J
成纤维细胞向肌成纤维细胞的转变被认为有助于哮喘和慢性阻塞性肺疾病等肺部疾病的气道重塑。本研究探讨了一种新的长效毒蕈碱拮抗剂aclidinium在人成纤维细胞向肌成纤维细胞转化中的作用。在有或没有吖啶酸（10−9至10−7 M）或不同药物调剂的情况下，用甲醇（10−8至10−5 M）或转化生长因子-β1 （TGF-β1; 2 ng/ml）刺激人支气管成纤维细胞48小时。通过I型胶原和α-平滑肌肌动蛋白（α-SMA） mRNA和蛋白表达以及α-SMA微丝免疫荧光分析，对肌成纤维细胞进行表征。western blot检测ERK1/2磷酸化、RhoA-GTP和毒毒碱受体(M) 1、2、3蛋白表达，ELISA检测3′-5′环单磷酸腺苷水平。对成纤维细胞的增殖和迁移也进行了评估。carbachol和TGF-β1以类似的方式上调I型胶原和α-SMA mRNA和蛋白的表达，以及α-SMA微丝阳性细胞的百分比，而aclidinium逆转了这些作用。carbachl诱导的肌成纤维细胞转化是通过ERK1/2磷酸化、RhoA-GTP激活和环单磷酸下调的增加以及自分泌TGF-β1的释放介导的，而aclidinium有效地减少了这些释放。TGF-β1激活非神经元胆碱能系统。抑制M1、M2或M3可部分阻止碳醇和TGF-β1诱导的肌成纤维细胞转化。吖啶酸剂量依赖性降低成纤维细胞增殖和迁移。Aclidinium抑制人肺成纤维细胞向肌成纤维细胞转化。
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. Human bronchial fibroblasts were stimulated with carbachol (10−8 to 10−5 M) or transforming growth factor-β1 (TGF-β1; 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 α-smooth muscle actin (α-SMA) mRNA and protein expression as well as α-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. Collagen type I and α-SMA mRNA and protein expression, as well as percentage α-SMA microfilament-positive cells, were upregulated in a similar way by carbachol and TGF-β1, 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-β1 release, which were effectively reduced by aclidinium. TGF-β1 activated the non-neuronal cholinergic system. Suppression of M1, M2 or M3 partially prevented carbachol- and TGF-β1-induced myofibroblast transition. Aclidinium dose-dependently reduced fibroblast proliferation and migration. Aclidinium inhibits human lung fibroblast to myofibrobast transition.
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DOI：
10.1152/ajplung.00417.2002
发表时间：
2003-08-01
影响因子：
4.9
作者：
Bogatkevich, GS;Tourkina, E;Ludwicka-Bradley, A
通讯作者：
Ludwicka-Bradley, A
DOI：
10.1152/ajpgi.00545.2006
发表时间：
2007-07-01
影响因子：
4.5
作者：
Akiho, Hirotada;Khan, Waliul I.;Collins, Stephen M.
通讯作者：
Collins, Stephen M.
影响因子：
10
作者：
Mata, M;Sarriá, B;Morcillo, EJ
通讯作者：
Morcillo, EJ
影响因子：
3.3
作者：
Lacmann, A.;Hess, D.;Krieglstein, K.
通讯作者：
Krieglstein, K.
影响因子：
24.3
作者：
Bos, I. S. T.;Gosens, R.;Zaagsma, J.
通讯作者：
Zaagsma, J.