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Published on: March 12, 2018
Transgenic hCFTR expression fails to correct β-ENaC mouse lung disease
B R Grubb1, W K O'Neal, L E Ostrowski
1Cystic Fibrosis/Pulmonary Research and Treatment Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7248, USA. bgrubb@med.unc.edu
Summary
Overexpressing human CFTR in mice increases chloride secretion but does not fix sodium absorption issues or lung disease in certain models. This highlights the complexity of airway ion transport and disease.
Area of Science:
- Pulmonary Medicine
- Ion Transport Physiology
- Genetics and Transgenic Models
Background:
- Airway epithelial ion transport, specifically the balance between chloride secretion and sodium absorption, is crucial for maintaining airway surface liquid (ASL) homeostasis.
- Dysregulation of this balance is implicated in various lung diseases, including cystic fibrosis.
- Understanding the role of the cystic fibrosis transmembrane conductance regulator (CFTR) in this balance is key to developing therapeutic strategies.
Purpose of the Study:
- To investigate the impact of transgenic overexpression of wild-type human CFTR (hCFTR) on airway epithelial ion transport and ASL homeostasis in mice.
- To determine if hCFTR expression can restore ion transport balance and ameliorate lung disease in a mouse model with epithelial sodium channel (ENaC) overexpression.
Main Methods:
- Generation of transgenic mice with airway-specific hCFTR expression using a Clara cell secretory protein (CCSP) promoter.
- Ussing chamber studies to measure ion transport currents in isolated mouse airways.
- Confocal microscopy to assess airway surface liquid (ASL) volume homeostasis in cultured tracheal cells.
- Cross-breeding of CCSP-hCFTR mice with mice overexpressing the β-subunit of ENaC (β-ENaC).
Main Results:
- Airway-specific hCFTR overexpression significantly increased basal chloride secretion (∼2.5-fold) but did not affect endogenous sodium absorption in wild-type mice.
- In CCSP-hCFTR/β-ENaC double transgenic mice, elevated chloride secretion and sodium hyperabsorption were observed.
- Despite increased chloride secretion, hCFTR expression did not correct the reduced ASL volume or ameliorate the lung disease characteristic of β-ENaC mice.
Conclusions:
- Airway hCFTR overexpression enhances basal chloride secretion but does not regulate sodium absorption in wild-type murine airways.
- Transgenic hCFTR expression in the context of β-ENaC overexpression increases chloride secretion but fails to restore ASL homeostasis or prevent lung disease, indicating that correcting sodium hyperabsorption is critical.
