CAMP STIMULATES BICARBONATE SECRETION ACROSS NORMAL, BUT NOT CYSTIC-FIBROSIS AIRWAY EPITHELIA
CAMP STIMULATES BICARBONATE SECRETION ACROSS NORMAL, BUT NOT CYSTIC-FIBROSIS AIRWAY EPITHELIA
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DOI：
10.1172/jci115696
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发表时间：
1992-04-01
影响因子：
15.9
通讯作者：
WELSH, MJ
中科院分区：
文献类型：
--
作者：
SMITH, JJ;WELSH, MJ
腺苷3‘，5’-环一磷酸刺激氯(Cl-)跨呼吸道上皮细胞分泌。为了确定cAMP是否也刺激HCO3的分泌，我们研究了在HCO3-/CO2缓冲的无氯溶液中浸泡的狗和人的呼吸道上皮细胞。加入Forsklin刺激短路电流的增加，这可能是碳酸氢盐分泌的结果，因为它被无HCO3的溶液、添加碳酸酐酶抑制剂乙酰唑胺或粘膜添加阴离子通道阻滞剂二苯胺2-羧酸盐所抑制。该电流依赖于Na+，因为它被从粘膜下洗液中去除Na+、添加Na+泵抑制剂哇巴因或向粘膜下液中添加1 mM阿米洛利所抑制。加入钙离子载体所产生的胞内钙离子增加也刺激了短路电流。这些数据表明，cAMP和钙离子刺激HCO3-通过呼吸道上皮分泌，并提示HCO3-通过传导途径穿过顶膜离开细胞。这些结果可能解释了先前的观察结果，即跨越呼吸道上皮的短路电流并不完全由Na+吸收和Cl-分泌之和所解释。囊性纤维化(CF)的气道上皮细胞没有cAMP诱导的分泌反应，但钙离子刺激的分泌是完整的。这一结果表明，HCO3-在顶膜上的退出是通过在CF上皮细胞中被缺陷调节的Cl-通道来实现的。这些结果提示，HCO3分泌缺陷可能参与了CF肺部疾病的病理生理过程。
Adenosine 3',5'-cyclic monophosphate stimulates chloride (Cl-) secretion across airway epithelia. To determine whether cAMP also stimulates HCO3- secretion, we studied cultured canine and human airway epithelial cells bathed in a HCO3-/CO2-buffered, Cl--free solution. Addition of forskolin stimulated an increase in short-circuit current that was likely a result of bicarbonate secretion because it was inhibited by a HCO3--free solution, by addition of the carbonic anhydrase inhibitor, acetazolamide, or by mucosal addition of the anion channel blocker, diphenylamine 2-carboxylate. The current was dependent on Na+ because it was inhibited by removal of Na+ from the submucosal bathing solution, by addition of the Na+ pump inhibitor, ouabain, or by addition of amiloride (1 mM) to the submucosal solution. An increase in cytosolic Ca2+ produced by addition of a Ca2+ ionophore also stimulated short-circuit current. These data suggest that cAMP and Ca2+ stimulate HCO3- secretion across airway epithelium, and suggest that HCO3- leaves the cell across the apical membrane via conductive pathways. These results may explain previous observations that the short-circuit current across airway epithelia was not entirely accounted for by the sum of Na+ absorption and Cl- secretion. The cAMP-induced secretory response was absent in cystic fibrosis (CF) airway epithelial cells, although Ca2+-stimulated secretion was intact. This result suggests that HCO3- exit at the apical membrane is through the Cl- channel that is defectively regulated in CF epithelia. These results suggest the possibility that a defect in HCO3- secretion may contribute to the pathophysiology of CF pulmonary disease.