肥大细胞源性的5-羟色胺增强乙酰甲胆碱诱导的屋尘螨诱发的实验性哮喘的气道高反应性
2021/02/09
摘要
背景：气道高反应性（AHR）是哮喘的特征，其中气道对刺激的高反应性导致广泛气道狭窄。乙酰甲胆碱激发主要通过直接刺激平滑肌细胞来评估哮喘患者的AHR。利用在体小鼠模型，肥大细胞与AHR有关，但其机制尚不清楚。
方法：利用缺乏肥大细胞的 Cpa3 Cre / +小鼠，评估肥大细胞在屋尘螨（HDM）诱导的实验性哮喘中的作用。在存在或不存在氯胺酮的情况下，评估乙酰甲胆碱对肺功能和体外肺肥大细胞的影响。评估气道炎症、肥大细胞聚集和活化、平滑肌增殖、HDM引起的支气管收缩。
结果：反复鼻内HDM致敏诱导与肺肥大细胞聚集和活化有关的过敏性气道炎症。肥大细胞缺乏、缺乏活化的Fc受体或拮抗血清素（5-HT）2A受体消除了HDM诱导的气管收缩。HDM致敏的小鼠缺乏肥大细胞，减少肺相关的5-HT含量、AHR降低和乙酰甲胆碱诱导气道收缩，同时阻断5-HT 2A野生型受体可消除AHR，表明肥大细胞通过释放5-HT来促进AHR。小鼠和人类肺肥大细胞表达毒蕈碱M3受体。小鼠肺肥大细胞可在细胞内储存5-HT，乙酰甲胆碱可诱导肺源性肥大细胞释放5-HT和人源性LAD-2肥大细胞的Ca2+释放。
结论：乙酰甲胆碱激活肥大细胞释放5-HT，其通过作用于5-HT 2A受体增强支气管收缩和AHR。因此，像噻托溴铵这样针对M3的哮喘治疗也可能通过靶向肥大细胞发挥作用。
(Allergy.2021 Jan 24.doi: 10.1111/all.14748. Online ahead of print.)
Mast cell-derived serotonin enhances methacholine-induced airway hyperresponsiveness in house dust mite-induced experimental asthma
Erika Mendez-Enriquez, Perla Abigail Alvarado-Vazquez, Willem Abma, Oscar E Simonson, Sergey Rodin, Thorsten B Feyerabend, Hans-Reimer Rodewald, Andrei Malinovschi, Christer Janson, Mikael Adner, Jenny Hallgren
Abstract
BACKGROUND: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.
METHODS:Cpa3Cre/+ mice, which lack mast cells, were used to assess the role of mast cells inhouse 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, HDM-induced bronchoconstriction were evaluated.
RESULTS: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)2A 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-HT2A 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 Ca2+ flux in human LAD-2 mast cells.
CONCLUSIONS:Methacholine activates mast cells to release 5-HT, which by acting on 5-HT2A receptors enhances bronchoconstriction and AHR. Thus, M3-directed asthma treatments like tiotropium may also act by targeting mast cells.
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中性粒细胞在哮喘中的作用
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哮喘诊断的第四维度
