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| Status |
Public on Mar 30, 2012 |
| Title |
Reduced Airway Surface pH Impairs Bacterial Killing in the Porcine Cystic Fibrosis Lung |
| Organism |
Sus scrofa |
| Experiment type |
Expression profiling by array
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| Summary |
Cystic fibrosis (CF) is a life-shortening disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. 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. We asked what abnormality impairs elimination when a bacterium lands on the pristine surface of a newborn CF airway? To investigate this defect, 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. At birth, their lungs lack infection and inflammation, but have a reduced ability to eradicate bacteria. 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 HCO3- transport. Without CFTR, airway epithelial HCO3- 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 ASL pH or bacterial killing could report on the benefit of therapeutic interventions.
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| Overall design |
11 samples of trachea primary airway epithelial cultures representing CFTR+/+ and CFTR-/- pigs. Pig samples representing 14 bronchus and 12 trachea tissue samples submitted in GSE21071.
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| Contributor(s) |
Ramachandran S |
| Citation(s) |
22763554 |
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| Submission date |
Mar 28, 2012 |
| Last update date |
May 03, 2013 |
| Contact name |
Shyam Ramachandran |
| E-mail(s) |
shyam-ramachandran@uiowa.edu
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| Phone |
3193356933
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| Organization name |
Univ of Iowa
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| Department |
Pediatrics
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| Lab |
McCray Lab
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| Street address |
240G EMRB
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| City |
Iowa City |
| ZIP/Postal code |
52242 |
| Country |
USA |
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| Platforms (1) |
| GPL3533 |
[Porcine] Affymetrix Porcine Genome Array |
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| Samples (11)
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| Relations |
| BioProject |
PRJNA157321 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE36906_RAW.tar |
20.1 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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