Muscarinic M3 Receptors Contribute to Allergen-Induced Airway Remodeling in Mice
Muscarinic M3 Receptors Contribute to Allergen-Induced Airway Remodeling in Mice
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DOI：
10.1165/rcmb.2013-0220oc
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发表时间：
2014-04-01
影响因子：
6.4
通讯作者：
Gosens, Reinoud
中科院分区：
文献类型：
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作者：
Kistemaker, Loes E. M.;Bos, Sophie T.;Gosens, Reinoud
哮喘是一种慢性阻塞性气道疾病，以炎症和重塑为特征。乙酰胆碱通过毒蕈碱M-3受体诱导支气管收缩，有助于症状的发生。最近的证据表明，支气管收缩可以调节气道重塑，因此暗示毒蕈碱M-3受体的作用。本研究的目的是利用毒蕈碱M-3受体亚型缺陷（M3R-/-）小鼠研究毒蕈碱M-3受体在过敏原诱导的重构中的作用。野生型（WT）、M1R-/-和M2R-/-小鼠作为对照。对C57Bl/ 6小鼠进行致敏和卵清蛋白攻击（每周两次，持续4周）。对照动物注射生理盐水。过敏原暴露诱导wt小鼠气道壁杯状细胞化生，气道平滑肌增厚（1.7倍），肺血管平滑肌重塑（1.5倍），I型胶原沉积（1.7倍）和纤维连接蛋白沉积（1.6倍）。这些效应在m (3)R（-/-）小鼠中不存在或明显降低（30-100%），而M1R-/-和M2R-/-小鼠的反应与WT小鼠相似。此外，与WT小鼠相比，M3R-/- 2盐胁迫小鼠气道平滑肌和肺血管平滑肌质量降低35-40%。有趣的是，过敏原诱导的气道炎症，通过嗜酸性粒细胞浸润和T辅助型2细胞因子表达来评估，在M3R-/-小鼠中相似甚至增强。我们的数据表明，乙酰胆碱通过毒蕈碱M-3受体，而不是通过M-1或M-2受体，促进过敏原诱导的重塑和平滑肌质量。未观察到毒蕈碱M-3受体在变应性炎症中的刺激作用，提示乙酰胆碱在重塑中的作用独立于变应性炎症反应，可能与支气管收缩有关。
Asthma is a chronic obstructive airway disease, characterized by inflammation and remodeling. Acetylcholine contributes to symptoms by inducing bronchoconstriction via the muscarinic M-3 receptor. Recent evidence suggests that bronchoconstriction can regulate airway remodeling, and therefore implies a role for the muscarinic M-3 receptor. The objective of this work was to study the contribution of the muscarinic M-3 receptor to allergen-induced remodeling using muscarinic M-3 receptor subtype-deficient (M3R-/-) mice. Wild-type (WT), M1R-/-, and M2R-/- mice were used as controls. C57Bl/ 6 mice were sensitized and challenged with ovalbumin (twice weekly for 4 wk). Control animals were challenged with saline. Allergen exposure induced goblet cell metaplasia, airway smooth muscle thickening (1.7-fold), pulmonary vascular smooth muscle remodeling (1.5-fold), and deposition of collagen I (1.7-fold) and fibronectin (1.6-fold) in the airway wall ofWT mice. These effects were absent or markedly lower inM(3)R(-/-) mice (30-100%), whereas M1R-/- and M2R-/- mice responded similarly to WT mice. In addition, airway smooth muscle and pulmonary vascular smooth muscle mass were 35-40% lower in saline-challenged M3R-/- 2 mice compared with WT mice. Interestingly, allergen-induced airway inflammation, assessed as infiltrated eosinophils and T helper type 2 cytokine expression, was similar or even enhanced in M3R-/- mice. Our data indicate that acetylcholine contributes to allergen-induced remodeling and smooth muscle mass via the muscarinic M-3 receptor, and not via M-1 or M-2 receptors. No stimulatory role for muscarinic M-3 receptors in allergic inflammation was observed, suggesting that the role of acetylcholine in remodeling is independent of the allergic inflammatory response, and may involve bronchoconstriction.