Journal
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Volume 190, Issue 4, Pages 421-432Publisher
AMER THORACIC SOC
DOI: 10.1164/rccm.201404-0670OC
Keywords
cystic fibrosis; airway epithelium; optical coherence tomography; mucus transport; viscosity
Categories
Funding
- National Heart, Lung, and Blood Institute [P01HL51811, R01HL116213, 5T32HL105346]
- National Institute of Diabetes and Digestive and Kidney Diseases [P30DK072482]
- National Institute of Bioimaging and Bioengineering of the National Institutes of Health [R01EB003558]
- Research Development Program [R464-CF]
- Mucociliary Clearance Consortium of the Cystic Fibrosis Foundation
- Flatley Foundation
- Dixon Foundation
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Rationale: The mechanisms underlying cystic fibrosis (CF) lung disease pathogenesis are unknown. Objectives: To establish mechanisms linking anion transport with the functional microanatomy, we evaluated normal and CF piglet trachea as well as adult swine trachea in the presence of selective anion inhibitors. Methods: We investigated airway functional microanatomy using microoptical coherence tomography, a new imaging modality that concurrently quantifies multiple functional parameters of airway epithelium in a colocalized fashion. Measurements and Main Results: Tracheal explants from wild-type swine demonstrated a direct link between periciliary liquid (PCL) hydration and mucociliary transport (MCT) rates, a relationship frequently invoked but never experimentally confirmed. However, in CF airways this relationship was completely disrupted, with greater PCL depths associated with slowest transport rates. This disrupted relationship was recapitulated by selectively inhibiting bicarbonate transport in vitro and ex vivo. CF mucus exhibited increased viscosity in situ due to the absence of bicarbonate transport, explaining defective MCT that occurs even in the presence of adequate PCL hydration. Conclusions: An inherent defect in CF airway surface liquid contributes to delayed MCT beyond that caused by airway dehydration alone and identifies a fundamental mechanism underlying the pathogenesis of CF lung disease in the absence of antecedent infection or inflammation.
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