CD38 plays an age-related role in cholinergic deregulation of airway smooth muscle contractility.
CD38 plays an age-related role in cholinergic deregulation of airway smooth muscle contractility.
复制标题
CD38在胆碱能调节气道平滑肌收缩性中发挥与年龄相关的作用。
DOI：
10.1016/j.jaci.2021.10.033
复制
发表时间：
2022-05
影响因子：
14.2
通讯作者：
Ai, Xingbin
中科院分区：
文献类型：
--
作者：
Bai, Yan;Guedes, Alonso G. P.;Krishnan, Ramaswamy;Ai, Xingbin
关键词：
过敏原诱导的新生小鼠气道高反应性（AHR），而不是成年小鼠，是由神经支配和随之而来的胆碱能过度刺激气道平滑肌（ASM）。是否这种炎症无关的机制有助于ASM过度收缩在儿童哮喘值得调查。我们的目的是建立胆碱能刺激和ASM收缩性在不同的人类年龄组之间的功能联系。首先，我们采用新生小鼠哮喘模型，以确定年龄相关的胆碱能失调的ASM收缩介质。接下来，我们在来自年轻（<5岁）和成年（>20岁）供体肺的原代人ASM细胞和精确切割肺切片（PCLS）中进行了验证和机制研究。最后，我们使用人类ASM过度收缩的培养模型评估了所鉴定的胆碱能信号传导介质的治疗潜力。我们已经发现，ASM过度收缩，由于胆碱能失调，在出生后的早期生活需要CD 38。在机制上，胆碱能信号激活未成熟ASM细胞中的PI 3 K/Akt通路以上调CD 38水平，从而增强对收缩激动剂的Ca 2+响应。值得注意的是，这种早期生命，CD 38介导的ASM过度收缩并没有被β-激动剂福莫特罗缓解。我们的研究结果表明，乙酰胆碱-PI 3 K/Akt-CD 38轴是出生后早期AHR的关键机制。针对这一轴可以为过敏性哮喘高危儿童提供量身定制的治疗。Akt（丝氨酸/苏氨酸激酶）、ASM（气道平滑肌）、cADPR（环ADP-核糖）、PI 3 K（磷酸肌醇3-激酶）、RyR（兰尼碱受体）、ACh（乙酰胆碱）、MCh（乙酰甲胆碱）、MR 3（毒蕈碱受体3）、His R（组胺受体）。乙酰胆碱-PI 3 K/Akt-CD 38通路是哮喘儿童抗AHR的潜在靶点。
Allergen-induced airway hyperresponsiveness (AHR) in neonatal mice, but not adult mice, is caused by elevated innervation and consequent cholinergic hyperstimulation of airway smooth muscle (ASM). Whether this inflammation-independent mechanism contributes to ASM hypercontraction in childhood asthma warrants investigation. We aim to establish the functional connection between cholinergic stimulation and ASM contractility in different human age groups. First, we employed a neonatal mouse model of asthma to identify age-related mediators of cholinergic deregulation of ASM contractility. Next, we conducted validation and mechanistic studies in primary human ASM cells and precision-cut lung slices (PCLSs) from young (<5 years old) and adult (>20 years old) donor lungs. Finally, we evaluated the therapeutic potential of the identified cholinergic signaling mediators using culture models of human ASM hypercontraction. We have discovered that ASM hypercontraction due to cholinergic deregulation in early postnatal life requires CD38. Mechanistically, cholinergic signaling activates the PI3K/Akt pathway in immature ASM cells to upregulate CD38 levels, thereby augmenting the Ca2+ response to contractile agonists. Strikingly, this early life, CD38-mediated ASM hypercontraction is not alleviated by the β-agonist, formoterol. Our findings identify the acetylcholine-PI3K/Akt-CD38 axis as a critical mechanism of AHR in early postnatal life. Targeting this axis may provide a tailored treatment for children at high risk for allergic asthma. Akt (A serine/threonine kinase), ASM (Airway smooth muscle), cADPR (Cyclic ADP-ribose), PI3K (Phosphoinositide 3-kinase), RyR (Ryanodine receptor), ACh (Acetylcholine), MCh (methacholine), MR3 (muscarinic receptor 3), His R (Histamine receptor). The acetylcholine-PI3K/Akt-CD38 pathway is a potential anti-AHR target in asthmatic children.
登录
查看更多内容
影响因子：
17.1
作者：
Drake MG;Scott GD;Blum ED;Lebold KM;Nie Z;Lee JJ;Fryer AD;Costello RW;Jacoby DB
通讯作者：
Jacoby DB
DOI：
10.1152/ajplung.00037.2012
发表时间：
2012-10-01
影响因子：
4.9
作者：
Hartman, William R.;Smelter, Dan F.;Pabelick, Christina M.
通讯作者：
Pabelick, Christina M.
影响因子：
4.8
作者：
Kong, Kok Choi;Billington, Charlotte K.;Penn, Raymond B.
通讯作者：
Penn, Raymond B.
DOI：
10.1124/jpet.118.249516
发表时间：
2018-12-01
影响因子：
3.5
作者：
Khindri, Sanjeev;Cahn, Anthony;Hessel, Edith M.
通讯作者：
Hessel, Edith M.
影响因子：
13.5
作者：
Deshpande DA;Guedes AGP;Lund FE;Subramanian S;Walseth TF;Kannan MS
通讯作者：
Kannan MS