Targeting acetylcholine receptor M3 prevents the progression of airway hyperreactivity in a mouse model of childhood asthma.
Targeting acetylcholine receptor M3 prevents the progression of airway hyperreactivity in a mouse model of childhood asthma.
复制标题
靶向乙酰胆碱受体 M3 可预防儿童哮喘小鼠模型中气道高反应性的进展。
DOI：
10.1096/fj.201700186r
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Ai,Xingbin
中科院分区：
文献类型：
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作者：
Patel,KrutiR;Bai,Yan;Trieu,KennethG;Barrios,Juliana;Ai,Xingbin
哮喘通常从早年不良环境暴露的发作发展到成年。然而，发育中的肺部损伤如何导致持续性哮喘的病理生理机制仍然知之甚少。在这项研究中，我们确定了沿胆碱能神经-气道平滑肌（ASM）轴的年龄相关机制，该机制是小鼠气道高反应性（AHR）延长的基础。我们发现，ASM直到出生后约3周才继续成熟。与出生后ASM成熟相一致，胆碱能刺激后ASM过度收缩的发展有一个关键的时间窗口。我们发现，在新生小鼠中，而在成年小鼠中，暴露于过敏原会提高胆碱能神经（称为神经可塑性）的水平和活性。我们在神经可塑性缺乏的小鼠的抢救试验中证明，胆碱能神经可塑性是诱导新生儿暴露后持续AHR的必要条件。此外，在新生儿暴露模型中，早期干预胆碱能受体毒蕈碱(ChRM)-3阻滞剂可以逆转AHR的进展，而β2-肾上腺素受体激动剂则没有这种作用。总之，我们的研究结果证明了胆碱能神经可塑性和ASM收缩表型之间的功能关系，这种关系在生命早期独特地起作用，在过敏原暴露后诱导持久性AHR。靶向ChRM3可能对儿童哮喘有改善疾病的益处。-Patel, k.r, Bai， Y., Trieu, k.g ., Barrios， J., Ai， X.靶向乙酰胆碱受体M3可阻止儿童哮喘小鼠模型气道高反应性的进展。
Asthma often progresses into adulthood from early-life episodes of adverse environmental exposures. However, how the injury to developing lungs contributes to the pathophysiology of persistent asthma remains poorly understood. In this study, we identified an age-related mechanism along the cholinergic nerve–airway smooth muscle (ASM) axis that underlies prolonged airway hyperreactivity (AHR) in mice. We showed that ASM continued to mature until ∼3 wk after birth. Coinciding with postnatal ASM maturation, there was a critical time window for the development of ASM hypercontractility after cholinergic stimulation. We found that allergen exposure in neonatal mice, but not in adult mice, elevated the level and activity of cholinergic nerves (termed neuroplasticity). We demonstrated that cholinergic neuroplasticity is necessary for the induction of persistent AHR after neonatal exposure during rescue assays in mice deficient in neuroplasticity. In addition, early intervention with cholinergic receptor muscarinic (ChRM)-3 blocker reversed the progression of AHR in the neonatal exposure model, whereas β2-adrenoceptor agonists had no such effect. Together, our findings demonstrate a functional relationship between cholinergic neuroplasticity and ASM contractile phenotypes that operates uniquely in early life to induce persistent AHR after allergen exposure. Targeting ChRM3 may have disease-modifying benefits in childhood asthma.—Patel, K. R., Bai, Y., Trieu, K. G., Barrios, J., Ai, X. Targeting acetylcholine receptor M3 prevents the progression of airway hyperreactivity in a mouse model of childhood asthma.