title: Chloride transport-driven alveolar fluid secretion is a major contributor to cardiogenic lung edema.
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.
authors: The Keenan Research Centre at the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, Canada M5B 1W8.
authors: Esther A
authors: EA
authors: Solymosi
authors: Stefanie M
authors: SM
authors: Kaestle-Gembardt
authors: István
authors: I
authors: Vadász
authors: Liming
authors: L
authors: Wang
authors: Nils
authors: N
authors: Neye
authors: Cécile Julie Adrienne
authors: CJ
authors: Chupin
authors: Simon
authors: S
authors: Rozowsky
authors: Ramona
authors: R
authors: Ruehl
authors: Arata
authors: A
authors: Tabuchi
authors: Holger
authors: H
authors: Schulz
authors: Andras
authors: A
authors: Kapus
authors: Rory E
authors: RE
authors: Morty
authors: Wolfgang M
authors: WM
authors: Kuebler
mesh_terms: D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D001826:Body Fluids / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004232:Diuretics / Q000494:pharmacology; D005665:Furosemide / Q000494:pharmacology; D006333:Heart Failure / Q000150:complications / Q000378:metabolism*; D006874:Hydrostatic Pressure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018181:Mice, Inbred CFTR; D011650:Pulmonary Alveoli / Q000378:metabolism*; D011654:Pulmonary Edema / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D020545:Respiratory Mucosa / Q000378:metabolism; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D064506:Solute Carrier Family 12, Member 2
chemical_list: C579654:CFTR protein, rat; D002712:Chlorides; D004232:Diuretics; C578878:Slc12a2 protein, mouse; C578879:Slc12a2 protein, rat; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000584:Amiloride; D005665:Furosemide; D000254:Sodium-Potassium-Exchanging ATPase
keywords: epithelial Cl- transport; pulmonary edema
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