Aclidinium inhibits cigarette smoke-induced lung fibroblast-to-myofibroblast transition
Aclidinium inhibits cigarette smoke-induced lung fibroblast-to-myofibroblast transition
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DOI：
10.1183/09031936.00017712
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发表时间：
2013-06-01
影响因子：
24.3
通讯作者：
Cortijo, Julio
中科院分区：
文献类型：
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作者：
Milara, Javier;Serrano, Adela;Cortijo, Julio
吸烟有助于慢性阻塞性肺疾病（COPD）的肺重塑。作为这种重塑的一部分，在COPD患者的小气道中观察到支气管周围纤维化，并导致气道阻塞。成纤维细胞向肌成纤维细胞转化是细支气管周围纤维化形成的关键步骤，本体外研究检测了香烟烟雾对支气管成纤维细胞向肌成纤维细胞转化的影响，以及阿地溴铵是否抑制了这一过程。将人支气管成纤维细胞与阿地溴铵（10（-9）-10（-7）M）孵育，并暴露于香烟烟雾提取物。I型胶原和α-平滑肌肌动蛋白（α-SMA）的表达通过实时PCR和蛋白质印迹法测定，作为肌成纤维细胞标志物。香烟烟雾诱导的I型胶原和α-SMA通过产生活性氧、消耗细胞内cAMP、增加ERK 1/2磷酸化和胆碱乙酰转移酶等途径介导细胞内信号传导。这些作用可通过抑制胆碱能药物阿地溴铵、抑制毒蕈碱受体M1、M2或M3的mRNA表达或通过乙酰胆碱酯酶清除细胞外乙酰胆碱来逆转。非神经元胆碱能系统参与香烟烟雾诱导的支气管成纤维细胞向肌成纤维细胞的转化，阿地溴铵可抑制这种转化。
Cigarette smoking contributes to lung remodelling in chronic obstructive pulmonary disease (COPD). As part of this remodelling, peribronchiolar fibrosis is observed in the small airways of COPD patients and contributes to airway obstruction. Fibroblast-to-myofibroblast transition is a key step in peribronchiolar fibrosis formation.This in vitro study examined the effect of cigarette smoke on bronchial fibroblast-to-myofibroblast transition, and whether aclidinium bromide inhibits this process. Human bronchial fibroblasts were incubated with aclidinium bromide (10(-9)-10(-7) M) and exposed to cigarette smoke extract. Collagen type I and alpha-smooth muscle actin (alpha-SMA) expression were measured by real-time PCR and Western blotting, as myofibroblast markers. Intracellular reactive oxygen species, cyclic AMP (cAMP), extracellular signal-regulated kinase (ERK)1/2 and choline acetyltransferase were measured as intracellular signalling mediators.Cigarette smoke-induced collagen type I and alpha-SMA was mediated by the production of reactive oxygen species, the depletion of intracellular cAMP and the increase of ERK1/2 phosphorylation and choline acetyltransferase. These effects could be reversed by treatment with the anticholinergic aclidinium bromide, by silencing the mRNA of muscarinic receptors M1, M2 or M3, or by the depletion of extracellular acetylcholine by treatment with acetylcholinesterase.A non-neuronal cholinergic system is implicated in cigarette smoke-induced bronchial fibroblast-to-myofibroblast transition, which is inhibited by aclidinium bromide.