title: Transgenic hCFTR expression fails to correct β-ENaC mouse lung disease.
abstract: The relationships between airway epithelial Cl(-) secretion-Na(+) absorption balance, airway surface liquid (ASL) homeostasis, and lung disease were investigated in selected transgenic mice. 1) To determine if transgenic overexpression of wild-type (WT) human CFTR (hCFTR) accelerated Cl(-) secretion and regulated Na(+) absorption in murine airways, we utilized a Clara cell secretory protein (CCSP)-specific promoter to generate mice expressing airway-specific hCFTR. Ussing chamber studies revealed significantly (∼2.5-fold) elevated basal Cl(-) secretory currents in CCSP-hCFTR transgenic mouse airways. Endogenous murine airway Na(+) absorption was not regulated by hCFTR, and these mice exhibited no lung disease. 2) We tested whether hCFTR, transgenically expressed on a transgenic mouse background overexpressing the β-subunit of the epithelial Na(+) channel (β-ENaC), restored ion transport balance and ASL volume homeostasis and ameliorated lung disease. Both transgenes were active in CCSP-hCFTR/β-ENaC transgenic mouse airways, which exhibited an elevated basal Cl(-) secretion and Na(+) hyperabsorption. However, the airway disease characteristic of β-ENaC mice persisted. Confocal studies of ASL volume homeostasis in cultured tracheal cells revealed ASL autoregulation to a height of ∼6 μm in WT and CCSP-hCFTR cultures, whereas ASL was reduced to <4 μm in β-ENaC and CCSP-hCFTR/β-ENaC cultures. We conclude that 1) hCFTR overexpression increases basal Cl(-) secretion but does not regulate Na(+) transport in WT mice and 2) transgenic hCFTR produces increased Cl(-) secretion, but not regulation of Na(+) channels, in β-ENaC mouse airways and does not ameliorate β-ENaC mouse lung disease.
authors: Cystic Fibrosis/Pulmonary Research and Treatment Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7248, USA. bgrubb@med.unc.edu
authors: B R
authors: BR
authors: Grubb
authors: W K
authors: WK
authors: O'Neal
authors: L E
authors: LE
authors: Ostrowski
authors: S M
authors: SM
authors: Kreda
authors: B
authors: B
authors: Button
authors: R C
authors: RC
authors: Boucher
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism*; D053503:Epithelial Sodium Channels / Q000235:genetics / Q000378:metabolism*; D005838:Genotype; D017136:Ion Transport / Q000235:genetics*; D008168:Lung / Q000378:metabolism; D008171:Lung Diseases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D012137:Respiratory System; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D014132:Trachea / Q000378:metabolism; D014598:Uteroglobin / Q000235:genetics
chemical_list: C505032:CFTR protein, human; D002712:Chlorides; D053503:Epithelial Sodium Channels; C556390:Scgb1a1 protein, mouse; D015222:Sodium Channels; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D014598:Uteroglobin; D012964:Sodium