Abstract
BackgroundAirway liquid hyper-absorption is a key pathophysiological link between the genetic mutations of cystic fibrosis (CF) and the development of lung disease. Here we consider whether the clearance of radiolabeled diethylene triamine pentaacetic acid (DTPA) might be used to detect changes in airway liquid absorption.MethodsTc99m-DTPA was added to the apical (luminal) surface of primary human bronchial epithelial cell cultures from CF and non-CF lungs. Liquid absorption rates were assessed using an optical method and compared to DTPA absorption rates. Measurements of transepithelial electrical resistance (TER) were made to determine the effect of epithelial permeability. DTPA absorption was assessed after stimuli known to influence liquid absorption (volume addition and osmotic gradients) and in cultures containing different proportions of CF and non-CF cells.ResultsDTPA absorption rate was increased in CF cultures matching previous in vivo studies in individuals with CF. DTPA and liquid absorption rates were proportional. There was no relationship between TER and DTPA absorption rate when measured in individual cultures. Apical volume addition increased both DTPA and liquid absorption rates. DTPA absorption increased in a dose-dependent manner after basolateral mannitol addition was used to create transepithelial osmotic gradients favoring liquid absorption. Conversely, apical mannitol (a candidate therapy) slowed DTPA absorption in CF cultures.ConclusionsThese results imply that DTPA absorption is directly related to liquid absorption, consistent with increased rates of airway surface liquid absorption in the CF airway, and that modification of liquid absorption from osmotic therapies might be detectable through DTPA absorption measurements in vivo.Trial registrationnone
Highlights
Airway liquid hyper-absorption is a key pathophysiological link between the genetic mutations of cystic fibrosis (CF) and the development of lung disease
diethylene triamine pentaacetic acid (DTPA) absorption rates in CF and non-CF human bronchial epithelial (HBE) cell cultures To determine whether DTPA absorption is different in CF primary airway cells compared to non-CF cells, the retention of DTPA on the apical surface was measured over time
There was no relationship between transepithelial electrical resistance (TER) and DTPA absorption rate across a large range of TER values, and the DTPA absorption rate was still significantly higher in CF cultures when compared to nonCF cultures with similar TER levels
Summary
Airway liquid hyper-absorption is a key pathophysiological link between the genetic mutations of cystic fibrosis (CF) and the development of lung disease. We consider whether the clearance of radiolabeled diethylene triamine pentaacetic acid (DTPA) might be used to detect changes in airway liquid absorption. By controlling Cl− and Na+ transport across the apical surface of epithelial cells, CFTR and ENaC establish the osmotic gradients that drive liquid transport across the airway epithelium. Liquid transport must support the hydration of the basic defects of CF lung disease. This would include the CFTR correctors and potentiators that have been the focus of recent therapeutic development efforts [10]. Tight junction conditions could substantially influence the paracellular absorption of DTPA and its ultimate clearance from the lung. Liquid transport through the tight junctions could influence rates of DTPA absorption. Airway liquid absorption can occur through both transcellular and paracellular routes. While the individual contributions of the routes have not been determined, the transcellular path is thought to dominate in CF [21]
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