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Cystic fibrosis swine fail to secrete airway surface liquid in response to inhalation of pathogens.

ABSTRACT: Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) channel, which can result in chronic lung disease. The sequence of events leading to lung disease is not fully understood but recent data show that the critical pathogenic event is the loss of the ability to clear bacteria due to abnormal airway surface liquid secretion (ASL). However, whether the inhalation of bacteria triggers ASL secretion and whether this is abnormal in cystic fibrosis has never been tested. Here we show, using a novel synchrotron-based in vivo imaging technique, that wild-type pigs display both a basal and a Toll-like receptor-mediated ASL secretory response to the inhalation of cystic fibrosis relevant bacteria. Both mechanisms fail in CFTR^-/- swine, suggesting that cystic fibrosis airways do not respond to inhaled pathogens, thus favoring infection and inflammation that may eventually lead to tissue remodeling and respiratory disease.Cystic fibrosis is caused by mutations in the CFTR chloride channel, leading to reduced airway surface liquid secretion. Here the authors show that exposure to bacteria triggers secretion in wild-type but not in pig models of cystic fibrosis, suggesting an impaired response to pathogens contributes to infection.

SUBMITTER: Luan X

PROVIDER: S-EPMC5629252 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Cystic fibrosis swine fail to secrete airway surface liquid in response to inhalation of pathogens.

Luan Xiaojie X Belev George G Tam Julian S JS Jagadeeshan Santosh S Hassan Noman N Gioino Paula P Grishchenko Nikolay N Huang Yanyun Y Carmalt James L JL Duke Tanya T Jones Teela T Monson Bev B Burmester Monique M Simovich Tomer T Yilmaz Orhan O Campanucci Veronica A VA Machen Terry E TE Chapman L Dean LD Ianowski Juan P JP

Nature communications 20171005 1

Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) channel, which can result in chronic lung disease. The sequence of events leading to lung disease is not fully understood but recent data show that the critical pathogenic event is the loss of the ability to clear bacteria due to abnormal airway surface liquid secretion (ASL). However, whether the inhalation of bacteria triggers ASL secretion and whether this is abnormal in ...[more]

PMID: 28983075

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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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Cystic fibrosis swine fail to secrete airway surface liquid in response to inhalation of pathogens.

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Cystic fibrosis swine fail to secrete airway surface liquid in response to inhalation of pathogens.

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