文章基本信息

标题：Chloride transport-driven alveolar fluid secretion is a major contributor to cardiogenic lung edema
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作者：Esther A. Solymosi ; Stefanie M. Kaestle-Gembardt ; István Vadász 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2013
卷号：110
期号：25
页码：E2308-E2316
DOI：10.1073/pnas.1216382110
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Alveolar fluid clearance driven by active epithelial Na+ and secondary Cl- absorption counteracts edema formation in the intact lung. Recently, we showed that impairment of alveolar fluid clearance because of inhibition of epithelial Na+ channels (ENaCs) promotes cardiogenic lung edema. Concomitantly, we observed a reversal of alveolar fluid clearance, suggesting that reversed transepithelial ion transport may promote lung edema by driving active alveolar fluid secretion. We, therefore, hypothesized that alveolar ion and fluid secretion may constitute a pathomechanism in lung edema and aimed to identify underlying molecular pathways. In isolated perfused lungs, alveolar fluid clearance and secretion were determined by a double-indicator dilution technique. Transepithelial Cl- secretion and alveolar Cl- influx were quantified by radionuclide tracing and alveolar Cl- imaging, respectively. Elevated hydrostatic pressure induced ouabain-sensitive alveolar fluid secretion that coincided with transepithelial Cl- secretion and alveolar Cl- influx. Inhibition of either cystic fibrosis transmembrane conductance regulator (CFTR) or Na+-K+-Cl- cotransporters (NKCC) blocked alveolar fluid secretion, and lungs of CFTR-/- mice were protected from hydrostatic edema. Inhibition of ENaC by amiloride reproduced alveolar fluid and Cl- secretion that were again CFTR-, NKCC-, and Na+-K+-ATPase-dependent. Our findings show a reversal of transepithelial Cl- and fluid flux from absorptive to secretory mode at hydrostatic stress. Alveolar Cl- and fluid secretion are triggered by ENaC inhibition and mediated by NKCC and CFTR. Our results characterize an innovative mechanism of cardiogenic edema formation and identify NKCC1 as a unique therapeutic target in cardiogenic lung edema.
关键词：epithelial Cl⁻ transport ; pulmonary edema