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Quantitative imaging of airway liquid absorption in cystic fibrosis.

ABSTRACT: New measures are needed to rapidly assess emerging treatments for cystic fibrosis (CF) lung disease. Using an imaging approach, we evaluated the absorptive clearance of the radiolabeled small molecule probe diethylene triamine penta-acetic acid (DTPA) as an in vivo indicator of changes in airway liquid absorption. DTPA absorption and mucociliary clearance rates were measured in 21 patients with CF (12 adults and nine children) and nine adult controls using nuclear imaging. The effect of hypertonic saline on DTPA absorption was also studied. In addition, in vitro studies were conducted to identify the determinants of transepithelial DTPA absorption. CF patients had significantly increased rates of DTPA absorption compared with control subjects but had similar mucociliary clearance rates. Treatment with hypertonic saline resulted in a decrease in DTPA absorption and an increase in mucociliary clearance in 11 out of 11 adult CF patients compared with treatment with isotonic saline. In vitro studies revealed that ? 50% of DTPA absorption can be attributed to transepithelial fluid transport. Apically applied mucus impedes liquid and DTPA absorption. However, mucus effects become negligible in the presence of an osmotic stimulus. Functional imaging of DTPA absorption provides a quantifiable marker of immediate response to treatments that promote airway surface liquid hydration.

SUBMITTER: Locke LW

PROVIDER: S-EPMC4150848 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Quantitative imaging of airway liquid absorption in cystic fibrosis.

Locke Landon W LW Myerburg Michael M MM Markovetz Matthew R MR Parker Robert S RS Weber Lawrence L Czachowski Michael R MR Harding Thomas J TJ Brown Stefanie L SL Nero Joseph A JA Pilewski Joseph M JM Corcoran Timothy E TE

The European respiratory journal 20140417 3

New measures are needed to rapidly assess emerging treatments for cystic fibrosis (CF) lung disease. Using an imaging approach, we evaluated the absorptive clearance of the radiolabeled small molecule probe diethylene triamine penta-acetic acid (DTPA) as an in vivo indicator of changes in airway liquid absorption. DTPA absorption and mucociliary clearance rates were measured in 21 patients with CF (12 adults and nine children) and nine adult controls using nuclear imaging. The effect of hyperton ...[more]

PMID: 24743971

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Project description:Respiratory failure, driven by airways mucus obstruction, chronic inflammation and bacterial infections, is the main cause of mortality and morbidity in people with cystic fibrosis (CF) due to defects in the Cl- and HCO3- transport activity of the CF Transmembrane conductance Regulator (CFTR). Most recent pre-clinical and clinical studies have focused on restoring CFTR function by enhancing its trafficking or transport activity and show promising results. However, there are a significant number of patients that will not benefit from these CFTR-targeted therapies and it is therefore important to identify new non-CFTR targets that will restore lung function, by-passing CFTR dysfunction. The H+/K+-ATPase, ATP12A, has recently been identified as a potential novel target for CF therapies, since its acute inhibition by ouabain was shown to help restore mucus viscosity, mucociliary transport, and antimicrobial activity using in vitro CF airway models, and this effect was linked to an increase in the pH of the airway surface liquid (ASL). Here, we have evaluated the potential therapeutic use of ouabain by investigating the effect of chronically treating fully differentiated CF primary human airway epithelial cells (hAECs) with ouabain, under thin film conditions, resembling the in vivo situation. Our results show that although chronic treatment increased ASL pH, this correlated with a deleterious effect on epithelial integrity as assessed by LDH release, transepithelial electrical resistance, fluorescein flux, and ion transport. Since ATP12A shares approximately 65% identity with the gastric H+/K+-ATPase (ATP4A), we investigated the potential of using clinically approved ATP4A proton pump inhibitors (PPIs) for their ability to restore ASL pH in CF hAECs. We show that, despite not expressing ATP4A transcripts, acute exposure to the PPI esomeprezole, produced changes in intracellular pH that were consistent with the inhibition of H+ secretion, but this response was independent of ATP12A. More importantly, chronic exposure of CF hAECs to esomeprazole alkalinized the ASL without disrupting the epithelial barrier integrity, but this increase in ASL pH was consistent with a decrease in mRNA expression of ATP12A. We conclude that PPIs may offer a new approach to restore ASL pH in CF airways, which is independent of CFTR.

Project description:Key pointsCl- and HCO3 - had similar paracellular permeabilities in human airway epithelia. PCl /PNa of airway epithelia was unaltered by pH 7.4 vs. pH 6.0 solutions. Under basal conditions, calculated paracellular HCO3 - flux was secretory. Cytokines that increased airway surface liquid pH decreased or reversed paracellular HCO3 - flux. HCO3 - flux through the paracellular pathway may counterbalance effects of cellular H+ and HCO3 - secretion.AbstractAirway epithelia control the pH of airway surface liquid (ASL), thereby optimizing respiratory defences. Active H+ and HCO3 - secretion by airway epithelial cells produce an ASL that is acidic compared with the interstitial space. The paracellular pathway could provide a route for passive HCO3 - flux that also modifies ASL pH. However, there is limited information about paracellular HCO3 - flux, and it remains uncertain whether an acidic pH produced by loss of cystic fibrosis transmembrane conductance regulator anion channels or proinflammatory cytokines might alter the paracellular pathway function. To investigate paracellular HCO3 - transport, we studied differentiated primary cultures of human cystic fibrosis (CF) and non-CF airway epithelia. The paracellular pathway was pH-insensitive at pH 6.0 vs. pH 7.4 and was equally permeable to Cl- and HCO3 - . Under basal conditions at pH ∼6.6, calculated paracellular HCO3 - flux was weakly secretory. Treating epithelia with IL-17 plus TNFα alkalinized ASL pH to ∼7.0, increased paracellular HCO3 - permeability, and paracellular HCO3 - flux was negligible. Applying IL-13 increased ASL pH to ∼7.4 without altering paracellular HCO3 - permeability, and calculated paracellular HCO3 - flux was absorptive. These results suggest that HCO3 - flux through the paracellular pathway counterbalances, in part, changes in the ASL pH produced via cellular mechanisms. As the pH of ASL increases towards that of basolateral liquid, paracellular HCO3 - flux becomes absorptive, tempering the alkaline pH generated by transcellular HCO3 - secretion.

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Quantitative imaging of airway liquid absorption in cystic fibrosis.

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Quantitative imaging of airway liquid absorption in cystic fibrosis.

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