Airway surface liquid volume regulation determines different airway phenotypes in liddle compared with betaENaC-overexpressing mice.
Studies in cystic fibrosis patients and mice overexpressing the epithelial Na(+) channel beta-subunit (betaENaC-Tg) suggest that raised airway Na(+) transport and airway surface liquid (ASL) depletion are central to the pathogenesis of cystic fibrosis lung disease. However, patients or mice with Liddle gain-of-function betaENaC mutations exhibit hypertension but no lung disease. To investigate this apparent paradox, we compared the airway phenotype (nasal versus tracheal) of Liddle with CFTR-null, betaENaC-Tg, and double mutant mice. In mouse nasal epithelium, the region that functionally mimics human airways, high levels of CFTR expression inhibited Liddle epithelial Nat channel (ENaC) hyperfunction. Conversely, in mouse trachea, low levels of CFTR failed to suppress Liddle ENaC hyperfunction. Indeed, Na(+) transport measured in Ussing chambers ("flooded" conditions) was raised in both Liddle and betaENaC-Tg mice. Because enhanced Na(+) transport did not correlate with lung disease in these mutant mice, measurements in tracheal cultures under physiologic "thin film" conditions and in vivo were performed. Regulation of ASL volume and ENaC-mediated Na(+) absorption were intact in Liddle but defective in betaENaC-Tg mice. We conclude that the capacity to regulate Na(+) transport and ASL volume, not absolute Na(+) transport rates in Ussing chambers, is the key physiologic function protecting airways from dehydration-induced lung disease.
Mall
Marcus A
MA
Division of Pediatric Pulmonology and Cystic Fibrosis Center, Department of Pediatrics III, University of Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany; Molecular Medicine Partnership Unit, University of Heidelberg and European Molecular Biology Laboratory, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany. Electronic address: Marcus.Mall@med.uni-heidelberg.de.
Button
Brian
B
Cystic Fibrosis/Pulmonary Research and Treatment Center, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248, Switzerland.
Johannesson
Bjarki
B
Division of Pediatric Pulmonology and Cystic Fibrosis Center, Department of Pediatrics III, University of Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany; Molecular Medicine Partnership Unit, University of Heidelberg and European Molecular Biology Laboratory, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany.
Zhou
Zhe
Z
Division of Pediatric Pulmonology and Cystic Fibrosis Center, Department of Pediatrics III, University of Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany.
Livraghi
Alessandra
A
Cystic Fibrosis/Pulmonary Research and Treatment Center, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248, Switzerland.
Caldwell
Ray A
RA
Cystic Fibrosis/Pulmonary Research and Treatment Center, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248, Switzerland.
Schubert
Susanne C
SC
Division of Pediatric Pulmonology and Cystic Fibrosis Center, Department of Pediatrics III, University of Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany.
Schultz
Carsten
C
Molecular Medicine Partnership Unit, University of Heidelberg and European Molecular Biology Laboratory, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany; Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
O'Neal
Wanda K
WK
Cystic Fibrosis/Pulmonary Research and Treatment Center, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248, Switzerland.
Pradervand
Sylvain
S
Department of Pharmacology and Toxicology, University of Lausanne, Bugnon 27, CH-1005 Lausanne, Switzerland.
Hummler
Edith
E
Department of Pharmacology and Toxicology, University of Lausanne, Bugnon 27, CH-1005 Lausanne, Switzerland.
Rossier
Bernard C
BC
Department of Pharmacology and Toxicology, University of Lausanne, Bugnon 27, CH-1005 Lausanne, Switzerland.
Grubb
Barbara R
BR
Cystic Fibrosis/Pulmonary Research and Treatment Center, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248, Switzerland.
Boucher
Richard C
RC
Cystic Fibrosis/Pulmonary Research and Treatment Center, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248, Switzerland.
D000818:Animals; D003550:Cystic Fibrosis / Q000378:metabolism / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D053503:Epithelial Sodium Channels / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D017136:Ion Transport / Q000235:genetics; D056929:Liddle Syndrome / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009297:Nasal Mucosa / Q000378:metabolism / Q000473:pathology; D009924:Organ Culture Techniques; D012964:Sodium / Q000378:metabolism*; D014132:Trachea / Q000378:metabolism / Q000473:pathology
D053503:Epithelial Sodium Channels; C507049:Scnn1b protein, mouse; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D012964:Sodium