title: Airway surface liquid volume regulation determines different airway phenotypes in liddle compared with betaENaC-overexpressing mice.
abstract: 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.
authors.affiliation: 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.
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Mall
authors.affiliation: Cystic Fibrosis/Pulmonary Research and Treatment Center, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248, Switzerland.
authors.forename: Brian
authors.initials: B
authors.lastname: Button
authors.affiliation: 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.
authors.forename: Bjarki
authors.initials: B
authors.lastname: Johannesson
authors.affiliation: Division of Pediatric Pulmonology and Cystic Fibrosis Center, Department of Pediatrics III, University of Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Cystic Fibrosis/Pulmonary Research and Treatment Center, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248, Switzerland.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Livraghi
authors.affiliation: Cystic Fibrosis/Pulmonary Research and Treatment Center, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248, Switzerland.
authors.forename: Ray A
authors.initials: RA
authors.lastname: Caldwell
authors.affiliation: Division of Pediatric Pulmonology and Cystic Fibrosis Center, Department of Pediatrics III, University of Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany.
authors.forename: Susanne C
authors.initials: SC
authors.lastname: Schubert
authors.affiliation: 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.
authors.forename: Carsten
authors.initials: C
authors.lastname: Schultz
authors.affiliation: Cystic Fibrosis/Pulmonary Research and Treatment Center, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248, Switzerland.
authors.forename: Wanda K
authors.initials: WK
authors.lastname: O'Neal
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Bugnon 27, CH-1005 Lausanne, Switzerland.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Pradervand
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Bugnon 27, CH-1005 Lausanne, Switzerland.
authors.forename: Edith
authors.initials: E
authors.lastname: Hummler
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Bugnon 27, CH-1005 Lausanne, Switzerland.
authors.forename: Bernard C
authors.initials: BC
authors.lastname: Rossier
authors.affiliation: Cystic Fibrosis/Pulmonary Research and Treatment Center, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248, Switzerland.
authors.forename: Barbara R
authors.initials: BR
authors.lastname: Grubb
authors.affiliation: Cystic Fibrosis/Pulmonary Research and Treatment Center, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248, Switzerland.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Boucher
mesh_terms: 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
chemical_list: D053503:Epithelial Sodium Channels; C507049:Scnn1b protein, mouse; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D012964:Sodium