Department of Molecular Pharmacology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
Pulm Pharmacol Ther. 2013 Feb;26(1):145-55. doi: 10.1016/j.pupt.2012.07.003. Epub 2012 Jul 25.
Since ancient times, anticholinergics have been used as a bronchodilator therapy for obstructive lung diseases. Targets of these drugs are G-protein-coupled muscarinic M(1), M(2) and M(3) receptors in the airways, which have long been recognized to regulate vagally-induced airway smooth muscle contraction and mucus secretion. However, recent studies have revealed that acetylcholine also exerts pro-inflammatory, pro-proliferative and pro-fibrotic actions in the airways, which may involve muscarinic receptor stimulation on mesenchymal, epithelial and inflammatory cells. Moreover, acetylcholine in the airways may not only be derived from vagal nerves, but also from non-neuronal cells, including epithelial and inflammatory cells. Airway smooth muscle cells seem to play a major role in the effects of acetylcholine on airway function. It has become apparent that these cells are multipotent cells that may reversibly adopt (hyper)contractile, proliferative and synthetic phenotypes, which are all under control of muscarinic receptors and differentially involved in bronchoconstriction, airway remodeling and inflammation. Cholinergic contractile tone is increased by airway inflammation associated with asthma and COPD, resulting from exaggerated acetylcholine release as well as increased expression of contraction related proteins in airway smooth muscle. Moreover, muscarinic receptor stimulation promotes proliferation of airway smooth muscle cells as well as fibroblasts, and regulates cytokine, chemokine and extracellular matrix production by these cells, which may contribute to airway smooth muscle growth, airway fibrosis and inflammation. In line, animal models of chronic allergic asthma and COPD have recently demonstrated that tiotropium may potently inhibit airway inflammation and remodeling. These observations indicate that muscarinic receptors have a much larger role in the pathophysiology of obstructive airway diseases than previously thought, which may have important therapeutic implications.
自古以来，抗胆碱能药物一直被用作治疗阻塞性肺部疾病的支气管扩张剂。这些药物的作用靶点是气道中的 G 蛋白偶联毒蕈碱 M(1)、M(2)和 M(3)受体，长期以来，人们一直认为这些受体调节迷走神经诱导的气道平滑肌收缩和黏液分泌。然而，最近的研究表明，乙酰胆碱在气道中也具有促炎、促增殖和促纤维化作用，这可能涉及到气道平滑肌细胞、上皮细胞和炎症细胞上的毒蕈碱受体刺激。此外，气道中的乙酰胆碱不仅可以来自迷走神经，还可以来自非神经细胞，包括上皮细胞和炎症细胞。气道平滑肌细胞似乎在乙酰胆碱对气道功能的影响中起着主要作用。显然，这些细胞是多能细胞，可以可逆地表现出（高）收缩性、增殖性和合成性表型，所有这些都受毒蕈碱受体的控制，并在支气管收缩、气道重塑和炎症中发挥不同的作用。与哮喘和 COPD 相关的气道炎症会增加胆碱能收缩张力，这是由于乙酰胆碱释放增加以及气道平滑肌中与收缩相关的蛋白表达增加所致。此外，毒蕈碱受体刺激促进气道平滑肌细胞和成纤维细胞的增殖，并调节这些细胞产生细胞因子、趋化因子和细胞外基质，这可能导致气道平滑肌生长、气道纤维化和炎症。相应地，慢性过敏性哮喘和 COPD 的动物模型最近表明，噻托溴铵可能能够有效地抑制气道炎症和重塑。这些观察结果表明，毒蕈碱受体在阻塞性气道疾病的病理生理学中发挥的作用比以前认为的要大得多，这可能具有重要的治疗意义。
