Pieper M P, Chaudhary N I, Park J E
Department of Pulmonary Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach an der Riss, Germany.
Life Sci. 2007 May 30;80(24-25):2270-3. doi: 10.1016/j.lfs.2007.02.034. Epub 2007 Mar 2.
Acetylcholine (ACh) has been suggested to exert various pathophysiological activities in the airways in addition to vagally-induced bronchoconstriction. This archetypal neurotransmitter and other components of the cholinergic system are expressed in a number of non-neuronal cells in the airways. Non-neuronal ACh released from these cells may affect fibroblasts (Fb) as well as inflammatory cells in lung tissue. Tiotropium bromide is a once-a-day antimuscarinic drug, marketed under the brand name Spiriva, for the treatment of chronic obstructive pulmonary disease (COPD). Besides its proven direct bronchodilatory activity, recent evidence suggests that tiotropium may be able to reduce the frequency of exacerbations and attenuate the decline in lung function, thus improving the course of obstructive airway diseases. The aim of the present study was to investigate the effects of tiotropium on the ACh-induced proliferation of primary human Fb isolated from biopsies of lung fibrosis patients and myofibroblasts (MyFb) derived from these cells. A human lung Fb cell line acted as control. Expression of muscarinic receptor subtypes M1, M2 and M3 was demonstrated by RT-PCR in both cell types. Acetylcholine stimulated proliferation in all cells investigated. Tiotropium concentration-dependently inhibited the ACh-induced proliferation in both the Fb and MyFb with a maximum effect at 30 nM. These results suggest that cholinergic stimuli mediated by muscarinic receptors could contribute to remodeling processes in chronic airway disease. Tiotropium bromide may have a beneficial influence on airway remodeling processes in chronic airway diseases through antiproliferative effects on fibroblasts and myofibroblasts.
除了迷走神经诱导的支气管收缩外，乙酰胆碱（ACh）还被认为在气道中发挥多种病理生理作用。这种典型的神经递质和胆碱能系统的其他成分在气道的许多非神经细胞中表达。从这些细胞释放的非神经ACh可能会影响成纤维细胞（Fb）以及肺组织中的炎症细胞。噻托溴铵是一种每日一次的抗毒蕈碱药物，商品名为思力华，用于治疗慢性阻塞性肺疾病（COPD）。除了已证实的直接支气管扩张活性外，最近的证据表明，噻托溴铵可能能够减少急性加重的频率，并减轻肺功能下降，从而改善阻塞性气道疾病的病程。本研究的目的是探讨噻托溴铵对从肺纤维化患者活检组织中分离的原代人Fb以及从这些细胞衍生的肌成纤维细胞（MyFb）中ACh诱导的增殖的影响。人肺Fb细胞系作为对照。通过RT-PCR在两种细胞类型中均证实了毒蕈碱受体亚型M1、M2和M3的表达。乙酰胆碱刺激了所有研究细胞的增殖。噻托溴铵浓度依赖性地抑制Fb和MyFb中ACh诱导的增殖，在30 nM时具有最大效应。这些结果表明，由毒蕈碱受体介导的胆碱能刺激可能有助于慢性气道疾病中的重塑过程。噻托溴铵可能通过对成纤维细胞和肌成纤维细胞的抗增殖作用，对慢性气道疾病中的气道重塑过程产生有益影响。
