Journal article

Publication year: 2013

Pages: E2308-E2316

Journal: Proceedings of the National Academy of Sciences

Volume number: 110

Issue number: 25

ISSN: 0027-8424

Open access status: Green

DOI Link: https://doi.org/10.1073/pnas.1216382110

Publisher: National Academy of Sciences

Abstract: 
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.

Harvard Citation style: Solymosi, E., Kaestle-Gembardt, S., Vadasz, I., Wang, L., Neye, N., Chupin, C., et al. (2013) Chloride transport-driven alveolar fluid secretion is a major contributor to cardiogenic lung edema, Proceedings of the National Academy of Sciences, 110(25), pp. E2308-E2316. https://doi.org/10.1073/pnas.1216382110

APA Citation style: Solymosi, E., Kaestle-Gembardt, S., Vadasz, I., Wang, L., Neye, N., Chupin, C., Rozowsky, S., Ruehl, R., Tabuchi, A., Schulz, H., Kapus, A., Morty, R., & Kuebler, W. (2013). Chloride transport-driven alveolar fluid secretion is a major contributor to cardiogenic lung edema. Proceedings of the National Academy of Sciences. 110(25), E2308-E2316. https://doi.org/10.1073/pnas.1216382110