ACTIVATION BY EXTRACELLULAR NUCLEOTIDES OF CHLORIDE SECRETION IN THE AIRWAY EPITHELIA OF PATIENTS WITH CYSTIC-FIBROSIS
ACTIVATION BY EXTRACELLULAR NUCLEOTIDES OF CHLORIDE SECRETION IN THE AIRWAY EPITHELIA OF PATIENTS WITH CYSTIC-FIBROSIS
复制标题
DOI：
10.1056/nejm199108223250802
复制
发表时间：
1991-08-22
影响因子：
158.5
通讯作者：
BOUCHER, RC
中科院分区：
文献类型：
--
作者：
KNOWLES, MR;CLARKE, LL;BOUCHER, RC
背景囊性纤维化的特征在于通过气道上皮的异常电解质转运。特别是，有过多的钠吸收和缺乏氯化物分泌。阻断过度钠吸收的药物可能在囊性纤维化中提供临床益处，但没有可用的治疗剂来改善氯化物分泌。体外培养的人气道上皮细胞研究表明，三磷酸核苷酸（ATP和UTP）通过顶膜嘌呤能受体诱导氯离子分泌。我们测试的能力，核苷酸诱导体内氯化物分泌在9名正常人和12例囊性纤维化患者通过测量反应的鼻跨上皮电位差（PD）的灌注核苷酸。用离子选择性微电极测定培养的鼻上皮细胞对细胞外（顶端）UTP的跨上皮生物电特性和顶端膜对氯离子的渗透性的变化。ATP和UTP诱导两组体内氯离子分泌。在最大有效浓度为10（-4）M时，ATP和UTP是囊性纤维化患者更有效的氯化物促分泌剂（PD的平均[+/- SE]变化，分别为-19.8 +/- 1.4 mV和-15.0 +/- 1.7 mV）（分别为-6.9 +/- 0.6 mV和-8.1 +/- 0.9 mV）。微电极研究证实，细胞外UTP刺激囊性纤维化患者上皮细胞PD和氯分泌电流的增加幅度大于正常人上皮细胞，其作用定位于顶膜。细胞外核苷酸是囊性纤维化患者鼻上皮中有效的体内氯化物促分泌素。ATP和UTP的等效性表明，该作用是由P2核苷酸受体介导的。选择核苷酸，如UTP或核苷酸类似物，应作为囊性纤维化肺部疾病的治疗药物进行研究。
Background. Cystic fibrosis is characterized by abnormal electrolyte transport across the epithelia of the airways. In particular, there is excessive sodium absorption and deficient chloride secretion. Drugs that block excessive sodium absorption may provide clinical benefit in cystic fibrosis, but there are no available therapeutic agents to improve chloride secretion. In vitro studies in cultured human-airway epithelia indicate that triphosphate nucleotides (ATP and UTP) induce chloride secretion through apical-membrane purinergic receptors.Methods. We tested the ability of nucleotides to induce chloride secretion in vivo in 9 normal subjects and 12 patients with cystic fibrosis by measuring responses of nasal transepithelial potential difference (PD) to superfusion of nucleotides. Changes in transepithelial bioelectric properties and the permeability of the apical membrane to chloride in response to extracellular (apical) UTP were determined with ion-selective microelectrodes in cultured nasal epithelia.Results. ATP and UTP induced chloride secretion in vivo in both groups. At their maximal effective concentrations of 10(-4) M, ATP and UTP were more effective chloride secretagogues in the patients with cystic fibrosis (mean [+/- SE] change in PD, -19.8 +/- 1.4 mV and -15.0 +/- 1.7 mV, respectively) than in the normal subjects (-6.9 +/- 0.6 mV and -8.1 +/- 0.9 mV, respectively). Microelectrode studies established that extracellular UTP stimulated a larger increase in PD and chloride secretory current in epithelial cells from patients with cystic fibrosis than in cells from normal subjects, by actions localized to the apical membrane.Conclusions. Extracellular nucleotides are effective in vivo chloride secretagogues in the nasal epithelia of patients with cystic fibrosis. The equipotency of ATP and UTP suggests that the effect is mediated by P2 nucleotide receptors. Selected nucleotides, such as UTP or nucleotide analogues, should be investigated as therapeutic agents for lung disease in cystic fibrosis.