Journal article
Reduced Airway Surface pH Impairs Bacterial Killing in the Porcine Cystic Fibrosis Lung
Nature (London), Vol.487(7405), pp.109-113
2012
DOI: 10.1038/nature11130
PMCID: PMC3390761
PMID: 22763554
Abstract
Cystic fibrosis (CF) is a life-shortening disease caused by mutations in the
cystic fibrosis transmembrane conductance regulator
(
CFTR
) gene
1
. Although bacterial lung infection and the resulting inflammation cause most of the morbidity and mortality, how loss of CFTR first disrupts airway host defense has remained uncertain
2
–
6
. We asked what abnormalities impair eradication when a bacterium lands on the pristine surface of a newborn CF airway? To investigate these defects, we interrogated the viability of individual bacteria immobilized on solid grids and placed on the airway surface. As a model we studied CF pigs, which spontaneously develop hallmark features of CF lung disease
7
,
8
. At birth, their lungs lack infection and inflammation, but have a reduced ability to eradicate bacteria
8
. Here we show that in newborn wild-type pigs, the thin layer of airway surface liquid (ASL) rapidly killed bacteria
in vivo
, when removed from the lung, and in primary epithelial cultures. Lack of CFTR reduced bacterial killing. We found that ASL pH was more acidic in CF, and reducing pH inhibited the antimicrobial activity of ASL. Reducing ASL pH diminished bacterial killing in wild-type pigs, and increasing ASL pH rescued killing in CF pigs. These results directly link the initial host defense defect to loss of CFTR, an anion channel that facilitates HCO
3
−
transport
9
–
13
. Without CFTR, airway epithelial HCO
3
−
secretion is defective, ASL pH falls and inhibits antimicrobial function, and thereby impairs killing of bacteria that enter the newborn lung. These findings suggest that increasing ASL pH might prevent the initial infection in patients with CF and that assaying bacterial killing could report on the benefit of therapeutic interventions.
Details
- Title: Subtitle
- Reduced Airway Surface pH Impairs Bacterial Killing in the Porcine Cystic Fibrosis Lung
- Creators
- Alejandro A Pezzulo - Department of Medicine, Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Xiao Xiao Tang - Departments of Molecular Physiology and Biophysics, Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Mark J Hoegger - Department of Medicine, Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Mahmoud H Abou Alaiwa - Department of Medicine, Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Shyam Ramachandran - Departments of Pediatrics, Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Thomas O Moninger - Central Electron Microscopy Facility, Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Phillip H Karp - Department of Medicine, Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Christine L Wohlford-Lenane - Departments of Pediatrics, Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Henk P Haagsman - Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht 3584 CL, The NetherlandsMartin van Eijk - Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht 3584 CL, The NetherlandsBotond Bánfi - Department of Medicine, Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Alexander R Horswill - Department of Microbiology, Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242David A Stoltz - Department of Medicine, Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Paul B McCray - Departments of Pediatrics, Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Michael J Welsh - Department of Medicine, Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Joseph Zabner - Department of Medicine, Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242
- Resource Type
- Journal article
- Publication Details
- Nature (London), Vol.487(7405), pp.109-113
- DOI
- 10.1038/nature11130
- PMID
- 22763554
- PMCID
- PMC3390761
- NLM abbreviation
- Nature
- ISSN
- 0028-0836
- eISSN
- 1476-4687
- Language
- English
- Date published
- 2012
- 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; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurosurgery; Otolaryngology; Internal Medicine
- Record Identifier
- 9984020771702771
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