Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
Unit of Experimental Asthma and Allergy Research, Institute of Environmental Medicine (IMM), Karolinska Institutet, Stockholm, Sweden.
Allergy. 2021 Jul;76(7):2057-2069. doi: 10.1111/all.14748. Epub 2021 Mar 9.
Airway hyperresponsiveness (AHR) is a feature of asthma in which airways are hyperreactive to stimuli causing extensive airway narrowing. Methacholine provocations assess AHR in asthma patients mainly by direct stimulation of smooth muscle cells. Using in vivo mouse models, mast cells have been implicated in AHR, but the mechanism behind has remained unknown.
Cpa3 mice, which lack mast cells, were used to assess the role of mast cells in house dust mite (HDM)-induced experimental asthma. Effects of methacholine in presence or absence of ketanserin were assessed on lung function and in lung mast cells in vitro. Airway inflammation, mast cell accumulation and activation, smooth muscle proliferation, and HDM-induced bronchoconstriction were evaluated.
Repeated intranasal HDM sensitization induced allergic airway inflammation associated with accumulation and activation of lung mast cells. Lack of mast cells, absence of activating Fc-receptors, or antagonizing serotonin (5-HT) receptors abolished HDM-induced trachea contractions. HDM-sensitized mice lacking mast cells had diminished lung-associated 5-HT levels, reduced AHR and methacholine-induced airway contraction, while blocking 5-HT receptors in wild types eliminated AHR, implying that mast cells contribute to AHR by releasing 5-HT. Primary mouse and human lung mast cells express muscarinic M3 receptors. Mouse lung mast cells store 5-HT intracellularly, and methacholine induces release of 5-HT from lung-derived mouse mast cells and Ca flux in human LAD-2 mast cells.
Methacholine activates mast cells to release 5-HT, which by acting on 5-HT receptors enhances bronchoconstriction and AHR. Thus, M3-directed asthma treatments like tiotropium may also act by targeting mast cells.
气道高反应性（AHR）是哮喘的一个特征，其中气道对引起广泛气道狭窄的刺激物高度敏感。乙酰甲胆碱激发试验主要通过直接刺激平滑肌细胞来评估哮喘患者的 AHR。在体内小鼠模型中，肥大细胞已被牵连到 AHR 中，但背后的机制仍不清楚。
使用缺乏肥大细胞的 Cpa3 小鼠来评估肥大细胞在屋尘螨（HDM）诱导的实验性哮喘中的作用。在体外评估了乙酰甲胆碱在有或没有酮色林存在的情况下对肺功能和肺肥大细胞的影响。评估了气道炎症、肥大细胞积聚和激活、平滑肌增殖以及 HDM 诱导的支气管收缩。
重复鼻内 HDM 致敏诱导了与肺肥大细胞积聚和激活相关的变应性气道炎症。缺乏肥大细胞、缺乏激活的 Fc 受体或拮抗 5-羟色胺（5-HT）受体消除了 HDM 诱导的气管收缩。缺乏肥大细胞的 HDM 致敏小鼠的肺相关 5-HT 水平降低，AHR 和乙酰甲胆碱诱导的气道收缩减少，而在野生型中阻断 5-HT 受体消除了 AHR，这表明肥大细胞通过释放 5-HT 导致 AHR。原代小鼠和人肺肥大细胞表达毒蕈碱 M3 受体。小鼠肺肥大细胞在细胞内储存 5-HT，乙酰甲胆碱诱导肺衍生的小鼠肥大细胞释放 5-HT 和 Ca 流进入人 LAD-2 肥大细胞。
乙酰甲胆碱激活肥大细胞释放 5-HT，5-HT 通过作用于 5-HT 受体增强支气管收缩和 AHR。因此，像噻托溴铵这样的 M3 定向哮喘治疗方法也可能通过靶向肥大细胞起作用。
