• Susan E Birket, Kengyeh K Chu, Linbo Liu, Grace H Houser, Bradford J Diephuis, Eric J Wilsterman, Gregory Dierksen, Marina Mazur, Suresh Shastry, Yao Li, John D Watson, Alexander T Smith, Benjamin S Schuster, Justin Hanes, William E Grizzle, Eric J Sorscher, Guillermo J Tearney, and Steven M Rowe.
• 1 Department of Medicine.
• Am. J. Respir. Crit. Care Med. 2014 Aug 15; 190 (4): 421-32.

RationaleThe mechanisms underlying cystic fibrosis (CF) lung disease pathogenesis are unknown.ObjectivesTo 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.MethodsWe 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 ResultsTracheal 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.ConclusionsAn 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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