Department of Molecular Pharmacology, University Centre for Pharmacy, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
Eur Respir J. 2011 Oct;38(4):789-96. doi: 10.1183/09031936.00146610. Epub 2011 Feb 24.
Airway remodelling and emphysema are major structural abnormalities in chronic obstructive pulmonary disease (COPD). In addition, pulmonary vascular remodelling may occur and contribute to pulmonary hypertension, a comorbidity of COPD. Increased cholinergic activity in COPD contributes to airflow limitation and, possibly, to inflammation and airway remodelling. This study aimed to investigate the role of acetylcholine in pulmonary inflammation and remodelling using an animal model of COPD. To this aim, guinea pigs were instilled intranasally with lipopolysaccharide (LPS) twice weekly for 12 weeks and were treated, by inhalation, with the long-acting muscarinic receptor antagonist tiotropium. Repeated LPS exposure induced airway and parenchymal neutrophilia, and increased goblet cell numbers, lung hydroxyproline content, airway wall collagen and airspace size. Furthermore, LPS increased the number of muscularised microvessels in the adventitia of cartilaginous airways. Tiotropium abrogated the LPS-induced increase in neutrophils, goblet cells, collagen deposition and muscularised microvessels, but had no effect on emphysema. In conclusion, tiotropium inhibits remodelling of the airways as well as pulmonary inflammation in a guinea pig model of COPD, suggesting that endogenous acetylcholine plays a major role in the pathogenesis of this disease.
气道重塑和肺气肿是慢性阻塞性肺疾病（COPD）的主要结构异常。此外，可能发生肺血管重塑，并导致肺动脉高压，这是 COPD 的一种合并症。COPD 中的胆碱能活性增加导致气流受限，并可能导致炎症和气道重塑。本研究旨在使用 COPD 动物模型研究乙酰胆碱在肺炎症和重塑中的作用。为此，豚鼠每周两次通过鼻腔内滴注脂多糖（LPS）12 周，并通过吸入长效毒蕈碱受体拮抗剂噻托溴铵进行治疗。重复 LPS 暴露诱导气道和实质嗜中性粒细胞增加，并增加杯状细胞数量、肺羟脯氨酸含量、气道壁胶原和气腔大小。此外，LPS 增加了软骨气道外膜中肌化微血管的数量。噻托溴铵消除了 LPS 诱导的嗜中性粒细胞、杯状细胞、胶原沉积和肌化微血管的增加，但对肺气肿没有影响。总之，噻托溴铵抑制了豚鼠 COPD 模型中气道重塑以及肺炎症，提示内源性乙酰胆碱在该疾病的发病机制中起主要作用。
