PuSH - Publication Server of Helmholtz Zentrum München

Export: TXT Text RIS Endnote (RIS) BIB BibTeX
Solymosi, E.A.* ; Kaestle-Gembardt, S.M.* ; Vadász, I.* ; Wang, L.* ; Neye, N.* ; Chupin, C.J.* ; Rozowsky, S.* ; Ruehl, R.* ; Tabuchi, A.* ; Schulz, H. ; Kapus, A.* ; Morty, R.E.* ; Kuebler, W.M.*

Chloride transport-driven alveolar fluid secretion is a major contributor to cardiogenic lung edema.

Proc. Natl. Acad. Sci. U.S.A. 110, E2308-E2316 (2013)
Publ. Version/Full Text Volltext DOI PMC
Open Access Gold
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.
Impact Factor
Scopus SNIP
Web of Science
Times Cited
Scopus
Cited By
Altmetric
9.737
2.641
39
54
Tags
Annotations
Special Publikation
Hide on homepage

Edit extra information
Edit own tags
Private
Edit own annotation
Private
Hide on publication lists
on hompage
Mark as special
publikation
Publication type Article: Journal article
Document type Scientific Article
Keywords Epithelial Cl- Transport ; Pulmonary Edema; Respiratory-distress-syndrome ; Acute Pulmonary-edema ; Ion-transport ; Na+ Absorption ; Epithelial Ion ; Ii Cells ; Cftr ; Furosemide ; Channels ; Volume
Language english
Publication Year 2013
HGF-reported in Year 2013
ISSN (print) / ISBN 0027-8424
e-ISSN 1091-6490
Journal Proceedings of the National Academy of Sciences of the United States of America
Quellenangaben Volume: 110, Issue: 25, Pages: E2308-E2316 Article Number: , Supplement: ,
Publisher National Academy of Sciences
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology (EPI)
POF-Topic(s) 30503 - Chronic Diseases of the Lung and Allergies
Research field(s) Genetics and Epidemiology
PSP Element(s) G-503900-003
PubMed ID 23645634
DOI 10.1073/pnas.1216382110
WOS ID WOS:000321500200012
Scopus ID 84879286719
Erfassungsdatum 2013-08-01
[➜Report correction]