CHLORIDE SECRETORY RESPONSE OF CYSTIC-FIBROSIS HUMAN AIRWAY EPITHELIA - PRESERVATION OF CALCIUM BUT NOT PROTEIN-KINASE C-DEPENDENT AND A-DEPENDENT MECHANISMS
CHLORIDE SECRETORY RESPONSE OF CYSTIC-FIBROSIS HUMAN AIRWAY EPITHELIA - PRESERVATION OF CALCIUM BUT NOT PROTEIN-KINASE C-DEPENDENT AND A-DEPENDENT MECHANISMS
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DOI：
10.1172/jci114316
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发表时间：
1989-11-01
影响因子：
15.9
通讯作者：
EARP, HS
中科院分区：
文献类型：
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作者：
BOUCHER, RC;CHENG, EHC;EARP, HS
由于囊性纤维化（CF）上皮细胞表现出的Cl-分泌缺陷反映了顶端膜Cl-通道的调节而不是传导异常，因此我们研究了不同调节途径在新鲜切除的正常和安装在Ussing腔中的CF鼻上皮细胞中Cl-分泌激活中的作用。A β。异丙肾上腺素（ISO）、钙离子载体（A23187）和佛波酯（PMA）都是正常人鼻上皮细胞有效的Cl-促分泌剂。激动剂添加研究表明，ISO和PMA而不是A23187可能具有共同的调控途径。相反，只有A23187诱导CF上皮细胞中的Cl-分泌。缓激肽升高细胞内Ca ~（2+）和诱导正常和CF组织中的Cl-分泌，表明CF中保留了受体门控的C2+依赖性Cl-分泌机制。CF上皮对ISO和PMA的Cl-分泌反应缺陷并不反映cAMP依赖性（A）和磷脂Ca 2+依赖性（C）激酶活性的异常。我们的结论是：（a）CF气道上皮细胞中维持了一种调节Cl-分泌的Ca 2+敏感机制，（B）CF中两种不同蛋白激酶共享的调节途径是有缺陷的，表明CF遗传性病变与单个（例如，cAMP依赖性）调节机制。
Because the defect in Cl- secretion exhibited by cystic fibrosis (CF) epithelia reflects regulatory rather than conductive abnormalities of an apical membrane Cl- channel, we investigated the role of different regulatory pathways in the activation of Cl- secretion in freshly excised normal and CF nasal epithelia mounted in Ussing chambers. A .beta. agonist (isoproterenol [ISO]), a Ca2+ ionophore (A23187), and a phorbolester (PMA) were all effective Cl- secretagogues in normal human nasal epithelia. Agonist addition studies indicated that ISO and PMA but not A23187 may share a common regulatory pathway. In contrast, only A23187 induced Cl- secretion in CF epithelia. Bradykinin raised cytosolic Ca2+ and induced Cl- secretion in both normal and CF tissues, indicating that receptor gated C2+ dependent Cl- secretory mechanisms were preserved in CF. The defective Cl- secretory response in CF epithelial to ISO and PMA did not reflect abnormalities in cAMP-dependent (A) and phospholipid Ca2+-dependent (C) kinase activities. We conclude that (a) a Ca2+-sensitive mechanism for regulating Cl- secretion is maintained in CF airway epithelia, and (b) a regualtory pathway shared by two distinct protein kinases is defective in CF, indicating that the CF genetic lesion is not tightly coupled to a single (e.g., cAMP dependent) regulatory mechanism.