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Updated: Feb 24, 2026
Real-Time, Semi-Automated Fluorescent Measurement of the Airway Surface Liquid pH of Primary Human Airway Epithelial Cells
Published on: June 13, 2019
Airway acidification initiates host defense abnormalities in cystic fibrosis mice
Viral S Shah1, David K Meyerholz2, Xiao Xiao Tang3
1Department of Medicine, University of Iowa, Iowa City, IA 52242, USA. Department of Molecular Physiology and Biophysics, Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Abstract:
Cystic fibrosis (CF) is caused by mutations in the gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. In humans and pigs, the loss of CFTR impairs respiratory host defenses, causing airway infection. But CF mice are spared. We found that in all three species, CFTR secreted bicarbonate into airway surface liquid. In humans and pigs lacking CFTR, unchecked H(+) secretion by the nongastric H(+)/K(+) adenosine triphosphatase (ATP12A) acidified airway surface liquid, which impaired airway host defenses. In contrast, mouse airways expressed little ATP12A and secreted minimal H(+); consequently, airway surface liquid in CF and non-CF mice had similar pH. Inhibiting ATP12A reversed host defense abnormalities in human and pig airways. Conversely, expressing ATP12A in CF mouse airways acidified airway surface liquid, impaired defenses, and increased airway bacteria. These findings help explain why CF mice are protected from infection and nominate ATP12A as a potential therapeutic target for CF.
Insights
Cystic fibrosis (CF) impairs airway defenses due to CFTR loss, but mice are spared. This study reveals that blocking H+/K+-ATPase (ATP12A) in humans and pigs restores defenses, identifying ATP12A as a therapeutic target for CF.
Area of Science:
- Physiology
- Molecular Biology
- Respiratory Medicine
Background:
- Cystic fibrosis (CF) is a genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.
- CFTR dysfunction impairs respiratory host defenses, leading to airway infections in humans and pigs, but not in mice.
Purpose of the Study:
- To investigate the underlying mechanisms explaining why CF mice are resistant to infection despite CFTR mutations.
- To identify potential therapeutic targets for CF by understanding species-specific differences in airway physiology.
Main Methods:
- Comparative analysis of airway surface liquid pH and ion transport in humans, pigs, and mice with and without CFTR.
- Inhibition of H+/K+-ATPase (ATP12A) in human and pig airway tissues.
- Expression of ATP12A in CF mouse airway epithelia.
Main Results:
- CFTR normally secretes bicarbonate into airway surface liquid across species.
- In CF humans and pigs, lack of CFTR leads to unchecked H+ secretion by ATP12A, acidifying airway surface liquid and impairing defenses.
- Mouse airways have minimal ATP12A activity, resulting in similar airway surface liquid pH in CF and non-CF mice, thus protecting them from infection.
Conclusions:
- Species-specific differences in ATP12A activity explain the absence of infection in CF mice.
- Inhibiting ATP12A in human and pig airways can reverse CF-related host defense abnormalities.
- ATP12A represents a promising therapeutic target for treating cystic fibrosis.
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