Activation of airway Cl- secretion in human subjects by adenosine
Activation of airway Cl- secretion in human subjects by adenosine
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DOI：
10.1165/rcmb.2004-0012oc
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发表时间：
2004-08-01
影响因子：
6.4
通讯作者：
Clancy, JP
中科院分区：
文献类型：
--
作者：
Hentchel-Franks, K;Lozano, D;Clancy, JP
我们研究了 CFTR 校正的 CFBE41o- 气道细胞和人类受试者中 A 腺苷 (Ado) 受体和 β(2) 肾上腺素能受体对囊性纤维化 (CF) 跨膜电导调节因子 (CFTR) 的调节。用Ado（10μM）、异丙肾上腺素（Iso，10μM）或Ado+Iso（各10μM）刺激的CFBE41o-细胞使环AMP（CAMP）升高至高于对照条件（P<0.001），其中Iso条件增加的CAMP类似于单独Ado产生的10倍（P<0.001）。所有激动剂条件对 10 和 25 μM 的短路电流都有相似的影响，随后用毛喉素 (20 μM) 刺激不会产生进一步的电流。 CFTR 依赖性通过格苯脲阻断激动剂刺激电流得到证实。正常 (n = 50) 受试者的鼻电位差研究表明，与 Iso 相比，Ado (10 μM) 和 Ado + Iso（各 10 μM）产生更多极化（10 μM Ado 增加 = 44%，10 μM Ado + Iso 增加 = 52%，与单独使用 Iso 相比，每种情况下 P < 0.05）。对 CF 患者（n = 10，“严重”基因型）完成的研究证实，Ado 刺激的极化是 CFTR 依赖性的。总之，这些结果表明 Ado 是体内有效的 Cl- 促分泌剂，尽管对 CFTR 依赖性短路电流和鼻 Cl- 转运有强烈影响，但对 CAMP 水平的影响相对较小。这些发现支持越来越多的证据表明 Ado 在体内调节 CFTR 依赖性 Cl 分泌的作用。
We investigated cystic fibrosis (CF) transmembrane conductance regulator (CFTR) regulation by A adenosine (Ado) receptors and beta(2) adrenergic receptors in CFTR-corrected CFBE41o- airway cells and human subjects. CFBE41o- cells stimulated with Ado (10 muM), isoproterenol (Iso, 10 muM), or Ado + Iso (10 muM each) elevated cyclic AMP (CAMP) above control conditions (P < 0.001), with the Iso conditions increasing CAMP similar to 10-fold above that produced by Ado alone (P < 0.001). All agonist conditions had similar effects on short circuit current at 10 and 25 muM, with no further currents produced by subsequent stimulation with forskolin (20 muM). CFTR dependence was demonstrated by glybenclamide block of agonist-stimulated currents. Nasal potential difference studies in normal (n = 50) subjects demonstrated that Ado (10 muM) and Ado + Iso (10 muM each) produced more polarization compared with lso (10 muM Ado increase = 44%, 10 muM Ado + Iso increase = 52%, P < 0.05 for each condition compared with Iso alone). Studies completed in patients with CF (n = 10, "severe" genotypes) confirmed that Ado-stimulated polarization was CFTR-dependent. Together, these results indicate that Ado is a potent Cl- secretagogue in vivo, with relatively small effects on CAMP levels despite strong effects on CFTR-dependent short circuit current and nasal Cl- transport. These findings support growing evidence indicating a role for Ado regulation of CFTR-dependent Cl- secretion in vivo.