Airway acidification initiates host defense abnormalities in cystic fibrosis mice

Viral S Shah; David K Meyerholz; Xiao Xiao Tang; Leah Reznikov; Mahmoud Abou Alaiwa; Sarah E Ernst; Philip H Karp; Christine L Wohlford-Lenane; Kristopher P Heilmann; Mariah R Leidinger; Patrick D Allen; Joseph Zabner; Paul B McCray Jr; Lynda S Ostedgaard; David A Stoltz; Christoph O Randak; Michael J Welsh

doi:10.1126/science.aad5589

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Airway acidification initiates host defense abnormalities in cystic fibrosis mice

Journal article

Open access

Peer reviewed

Airway acidification initiates host defense abnormalities in cystic fibrosis mice

Viral S Shah, David K Meyerholz, Xiao Xiao Tang, Leah Reznikov, Mahmoud Abou Alaiwa, Sarah E Ernst, Philip H Karp, Christine L Wohlford-Lenane, Kristopher P Heilmann, Mariah R Leidinger, …

Science (American Association for the Advancement of Science), Vol.351(6272), pp.503-507

01/29/2016

DOI: 10.1126/science.aad5589

PMCID: PMC4852973

PMID: 26823428

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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.

Lung - microbiology

H(+)-K(+)-Exchanging ATPase - metabolism

Mice, Inbred CFTR - genetics

Cystic Fibrosis - metabolism

Cystic Fibrosis - microbiology

Mice, Inbred CFTR - metabolism

Humans

Mice, Transgenic

H(+)-K(+)-Exchanging ATPase - genetics

Acids - metabolism

Animals

Swine

Bicarbonates - metabolism

Lung - metabolism

Mice

Hydrogen-Ion Concentration

Details

Title: Subtitle: Airway acidification initiates host defense abnormalities in cystic fibrosis mice
Creators: Viral S Shah - 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
David K Meyerholz - Department of Pathology, University of Iowa, Iowa City, IA 52242, USA
Xiao Xiao Tang - Department of Medicine, University of Iowa, Iowa City, IA 52242, USA. Howard Hughes Medical Institute, University of Iowa, Iowa City, IA 52242, USA
Leah Reznikov - Department of Medicine, University of Iowa, Iowa City, IA 52242, USA
Mahmoud Abou Alaiwa - Department of Medicine, University of Iowa, Iowa City, IA 52242, USA
Sarah E Ernst - Department of Medicine, University of Iowa, Iowa City, IA 52242, USA. Howard Hughes Medical Institute, University of Iowa, Iowa City, IA 52242, USA
Philip H Karp - Department of Medicine, University of Iowa, Iowa City, IA 52242, USA. Howard Hughes Medical Institute, University of Iowa, Iowa City, IA 52242, USA
Christine L Wohlford-Lenane - Department of Pediatrics University of Iowa, Iowa City, IA 52242, USA
Kristopher P Heilmann - Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA
Mariah R Leidinger - Department of Pathology, University of Iowa, Iowa City, IA 52242, USA
Patrick D Allen - Department of Medicine, University of Iowa, Iowa City, IA 52242, USA
Joseph Zabner - Department of Medicine, University of Iowa, Iowa City, IA 52242, USA
Paul B McCray Jr - Department of Pediatrics University of Iowa, Iowa City, IA 52242, USA. Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA
Lynda S Ostedgaard - Department of Medicine, University of Iowa, Iowa City, IA 52242, USA
David A Stoltz - 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
Christoph O Randak - Department of Pediatrics University of Iowa, Iowa City, IA 52242, USA
Michael J Welsh - 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
Resource Type: Journal article
Publication Details: Science (American Association for the Advancement of Science), Vol.351(6272), pp.503-507
DOI: 10.1126/science.aad5589
PMID: 26823428
PMCID: PMC4852973
NLM abbreviation: Science
ISSN: 0036-8075
eISSN: 1095-9203
Publisher: United States
Grant note: 5T32GM007337 / NIGMS NIH HHS Howard Hughes Medical Institute K08 HL097071 / NHLBI NIH HHS T32 GM007337 / NIGMS NIH HHS K08HL097071 / NHLBI NIH HHS HL51670 / NHLBI NIH HHS DP2 HL117744 / NHLBI NIH HHS P01 HL091842 / NHLBI NIH HHS HL091842 / NHLBI NIH HHS HL117744 / NHLBI NIH HHS F30HL123239 / NHLBI NIH HHS P01 HL051670 / NHLBI NIH HHS DK054759 / NIDDK NIH HHS P30 DK054759 / NIDDK NIH HHS F30 HL123239 / NHLBI NIH HHS K99 HL119560 / NHLBI NIH HHS
Language: English
Date published: 01/29/2016
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Neurology; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Microbiology and Immunology; Pulmonary Medicine; Stead Family Department of Pediatrics; Pathology; Neurosurgery; Internal Medicine
Record Identifier: 9984020799702771

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