Asthmatic Augmentation of Airway Vagal Activity Involves Decreased Central Expression and Activity of CD73 in Rats
Asthmatic Augmentation of Airway Vagal Activity Involves Decreased Central Expression and Activity of CD73 in Rats
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哮喘患者气道迷走神经活动增强涉及 CD73 中枢表达和活性降低
DOI：
10.1021/acschemneuro.9b00023
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发表时间：
2019
影响因子：
5
通讯作者：
Wang Jijiang
中科院分区：
文献类型：
--
作者：
Chen Xingxin;Zeng Ming;He Ding;Yan Xianxia;Chen Hong;Chen Yonghua;Xia Chunmei;Wang Jin;Shen Linlin;Zhu Danian;Wang Jijiang
哮喘的严重程度与气道迷走神经活动的强度密切相关；然而，目前尚不清楚哮喘患者的气道迷走神经活动是如何集中增强的。本研究报道，在雄性Sprague-Dawley大鼠哮喘模型中，迷走神经中枢外链5′-核苷酸酶（CD73）的表达和活性降低，脑脊液中ATP浓度升高，内源性注射ATP （5 μmol）和CD73抑制剂AMPCP （5 μmol）后，迷走神经的抑制和兴奋性反应减弱。在新生儿Sprague-Dawley大鼠髓质切片中鉴定的气道迷走神经节前神经元（AVPNs）中，AMPCP （100 μmol·L-1）引起兴奋作用，如去极化膜片钳，神经元放电增加，促进自发兴奋性突触后电流（sEPSCs）。而外源ATP （100 μmol·L-1、1 mmol·L-1）的抑制作用与外源腺苷（100 μmol·L-1）的抑制作用相似。腺苷a1受体拮抗剂CPT （5 μmol·L-1）可阻断100 μmol·L-1外源ATP和100 μmol·L-1外源腺苷诱导的sEPSCs的抑制作用，而50 μmol·L-1CPT可将1 mmol·L-1ATP诱导的sEPSCs的抑制作用转化为P2X受体拮抗剂PPADS （20 μmol·L-1）阻断的促进作用。这些结果表明，在大鼠体内，细胞外ATP通过激活P2X受体促进了AVPNs的sEPSCs，细胞外腺苷通过激活a1受体抑制了AVPNs的sEPSCs；在实验性哮喘中，气道迷走神经中心CD73表达和活性的降低通过ATP/ADO对AVPNs的不平衡调节，有助于气道迷走神经活性的增强。
The severity of asthma is closely related to the intensity of airway vagal activity; however, it is unclear how airway vagal activity is centrally augmented in asthma. Here we report that in an asthma model of male Sprague–Dawley rats, the expression and activity of ecto-5′-nucleotidase (CD73) were decreased in airway vagal centers, ATP concentration in cerebral spinal fluid was increased, and the inhibitory and excitatory airway vagal responses to intracisternally injected ATP (5 μmol) and CD73 inhibitor AMPCP (5 μmol), respectively, were attenuated. In airway vagal preganglionic neurons (AVPNs) identified in medullary slices of neonatal Sprague–Dawley rats, AMPCP (100 μmol·L–1) caused excitatory effects, as are shown in patch-clamp by depolarization, increased neuronal discharge, and facilitated spontaneous excitatory postsynaptic currents (sEPSCs). In contrast, exogenous ATP (100 μmol·L–1, 1 mmol·L–1) primarily caused inhibitory effects, which are similar to those induced by exogenous adenosine (100 μmol·L–1). Adenosine A1receptor antagonist CPT (5 μmol·L–1) blocked the inhibition of sEPSCs induced by 100 μmol·L–1exogenous ATP and that by 100 μmol·L–1exogenous adenosine, whereas 50 μmol·L–1CPT converted the inhibition of sEPSCs induced by 1 mmol·L–1ATP to facilitation that was blocked by addition of P2X receptor antagonist PPADS (20 μmol·L–1). These results demonstrate that in rat, the sEPSCs of AVPNs are facilitated by extracellular ATP via activation of P2X receptors and inhibited by extracellular adenosine via activation of A1receptors; in experimental asthma, decreased CD73 expression and activity in airway vagal centers contribute to the augmentation of airway vagal activity through imbalanced ATP/ADO modulation of AVPNs.