title: Airway acidification initiates host defense abnormalities in cystic fibrosis mice.
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.
authors.affiliation: Department 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.
authors.forename: Viral S
authors.initials: VS
authors.lastname: Shah
authors.affiliation: Department of Pathology, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: David K
authors.initials: DK
authors.lastname: Meyerholz
authors.affiliation: Department of Medicine, University of Iowa, Iowa City, IA 52242, USA. Howard Hughes Medical Institute, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Xiao Xiao
authors.initials: XX
authors.lastname: Tang
authors.affiliation: Department of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Leah
authors.initials: L
authors.lastname: Reznikov
authors.affiliation: Department of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Abou Alaiwa
authors.affiliation: Department of Medicine, University of Iowa, Iowa City, IA 52242, USA. Howard Hughes Medical Institute, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Ernst
authors.affiliation: Department of Medicine, University of Iowa, Iowa City, IA 52242, USA. Howard Hughes Medical Institute, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Philip H
authors.initials: PH
authors.lastname: Karp
authors.affiliation: Department of Pediatrics University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Wohlford-Lenane
authors.affiliation: Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Kristopher P
authors.initials: KP
authors.lastname: Heilmann
authors.affiliation: Department of Pathology, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Mariah R
authors.initials: MR
authors.lastname: Leidinger
authors.affiliation: Department of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Allen
authors.affiliation: Department of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Zabner
authors.affiliation: Department of Pediatrics University of Iowa, Iowa City, IA 52242, USA. Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Paul B
authors.initials: PB
authors.lastname: McCray
authors.affiliation: Department of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Lynda S
authors.initials: LS
authors.lastname: Ostedgaard
authors.affiliation: Department 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. Department of Biomedical Engineering, College of Engineering, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Stoltz
authors.affiliation: Department of Pediatrics University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Christoph O
authors.initials: CO
authors.lastname: Randak
authors.affiliation: Department 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. Howard Hughes Medical Institute, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Welsh
mesh_terms: D000143:Acids / Q000378:metabolism; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D003550:Cystic Fibrosis / Q000378:metabolism* / Q000382:microbiology*; D017506:H(+)-K(+)-Exchanging ATPase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008168:Lung / Q000378:metabolism* / Q000382:microbiology*; D051379:Mice; D018181:Mice, Inbred CFTR / Q000235:genetics / Q000378:metabolism; D008822:Mice, Transgenic; D013552:Swine
chemical_list: D000143:Acids; D001639:Bicarbonates; C088641:ATP12A protein, human; D017506:H(+)-K(+)-Exchanging ATPase
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