Transgenic hCFTR expression fails to correct β -ENaC mouse lung disease

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.