Abnormal ion content, hydration and granule expansion of the secretory granules from cystic fibrosis airway glandular cells

Baconnais, Sonia; Delavoi, F.; Zahm, Jean‐Marie; Milliot, Magali; Terryn, Christine; Castillon, Nicolas; Banchet, Vincent; Michel, Jean; Danos, Olivier; Merten, Marc; Chinet, Thierry; Zierold, Karl; Bonnet, N.; Puchelle, Édith; Balossier, G.

doi:10.1016/j.yexcr.2005.06.010

Cited by 20 publications

(24 citation statements)

References 34 publications

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“…In solutions of identical ionic composition, Verdugo demonstrated that extracellular Ca 2+ inhibition of the swelling of CF mucin granules was about 5 times greater relative to mucin granules from normal human airway goblet cells, thereby indicating increased mucin-Ca 2+ affinity in CF granules (72). Consonant with this, electron microprobe analysis has found higher Ca 2+ content in CF airway secretory granules (73). An alkaline pH in Cftr-KO granules and the secretory pathway would be predicted to increase mucin-Ca 2+ affinity by mucin deprotonation (74,75) and increased mucin sulfation (67,76).…”

Section: Discussionmentioning

confidence: 84%

Defective goblet cell exocytosis contributes to murine cystic fibrosis–associated intestinal disease

Liu¹,

Walker²,

Ootani³

et al. 2015

J. Clin. Invest.

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Section: Discussionmentioning

confidence: 84%

Defective goblet cell exocytosis contributes to murine cystic fibrosis–associated intestinal disease

Liu¹,

Walker²,

Ootani³

et al. 2015

J. Clin. Invest.

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“…S3 shows that αBTX dose-dependently decreased forskolin-activated chloride efflux in MM39, a cell line derived from the normal human airway glandular epithelium and expressing WT-CFTR (23). It had no effect on KM4, a cell line derived from CF human tracheal glands and homozygous for the ΔF508 mutation (24), and decreased forskolin-activated chloride efflux in KM4*, derived from the KM4 cell line after transduction with the lentiviral vector expressing the WT-CFTR cDNA (25). These αBTX effects were abolished after inhibiting CFTR with the CFTR inh -172 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Contribution of α7 nicotinic receptor to airway epithelium dysfunction under nicotine exposure

Maouche

Medjber

Zahm

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Loss or dysfunction of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) leads to impairment of airway mucus transport and to chronic lung diseases resulting in progressive respiratory failure. Nicotinic acetylcholine receptors (nAChRs) bind nicotine and nicotine-derived nitrosamines and thus mediate many of the tobacco-related deleterious effects in the lung. Here we identify α7 nAChR as a key regulator of CFTR in the airways. The airway epithelium in α7 knockout mice is characterized by a higher transepithelial potential difference, an increase of amiloride-sensitive apical Na + absorption, a defective cAMP-dependent Cl − conductance, higher concentrations of Na + , Cl − , K + , and Ca 2+ in secretions, and a decreased mucus transport, all relevant to a deficient CFTR activity. Moreover, prolonged nicotine exposure mimics the absence of α7 nAChR in mice or its inactivation in vitro in human airway epithelial cell cultures. The functional coupling of α7 nAChR to CFTR occurs through Ca 2+ entry and activation of adenylyl cyclases, protein kinase A, and PKC. α7 nAChR, CFTR, and adenylyl cyclase-1 are physically and functionally associated in a macromolecular complex within lipid rafts at the apical membrane of surface and glandular airway epithelium. This study establishes the potential role of α7 nAChR in the regulation of CFTR function and in the pathogenesis of smoking-related chronic lung diseases.chloride efflux | ciliated cell | mouse | mucociliary clearance | submucosal gland

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“…Emerging evidence suggests that CF lung pathophysiology is linked to dehydration of airway surfaces caused by epithelial ion transport defects (Baconnais et al, 2005;Boucher, 2007;Donaldson et al, 2007). One pharmacologic approach to rehydrate airway surfaces is aerosol ENaC blocker therapy.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Properties ofN-(3,5-Diamino-6-chloropyrazine-2-carbonyl)-N′-4-[4-(2,3-dihydroxypropoxy)phenyl]butyl-guanidine Methanesulfonate (552-02), a Novel Epithelial Sodium Channel Blocker with Potential Clinical Efficacy for Cystic Fibrosis Lung Disease

Hirsh¹,

Zhang²,

Zamurs³

et al. 2008

J Pharmacol Exp Ther

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Amiloride improves mucociliary clearance (MC) by blocking airway epithelial sodium channels (ENaC) and expanding airway surface liquid (ASL). However, the low potency and rapid absorption of amiloride by airway epithelia translated into a short duration of efficacy as an aerosolized therapy for cystic fibrosis (CF) patients. To improve ENaC blocker CF pharmacotherapy, a more potent and durable ENaC blocker tailored for aerosol delivery was synthesized. Parion compound N-(3,5-diamino-6-chloropyrazine-2-carbonyl)-NЈ-4-[4-(2,3-dihydroxypropoxy)phenyl]butyl-guanidine methanesulfonate (552-02) was tested for potency and reversibility of ENaC block, epithelial absorption and biotransformation, selectivity, durability of ASL expansion under isotonic and hypertonic conditions in canine and human CF bronchial epithelial cells, and drug dissociation on ENaC in Xenopus oocytes. Short-circuit current assessed compound potency and reversibility, patch-clamp recordings of ENaC current assessed drug off-rate (k off ), a gravimetric method and confocal microscopy measured mucosal water retention and ASL height, and drug absorption and biotransformation were assessed using liquid chromatography-mass spectrometry. Amiloride and 552-02 were tested in vivo for MC activity in sheep immediately and 4 to 6 h after aerosol dosing. Compared with amiloride, compound 552-02 was 60 to 100-fold more potent, it was 2 to 5-fold less reversible, it was slower at crossing the epithelium, and it exhibited a 170-fold slower k off value. 552-02 exhibited greater ASL expansion over 8 h in vitro, and it was more effective than amiloride at increasing MC immediately and 4 to 6 h after dosing. When combining hypertonic saline and 552-02, a synergistic effect on ASL expansion was measured in canine or CF bronchial epithelia. In summary, the preclinical data support the clinical use of 552-02 ϩ/Ϫ hypertonic saline for CF lung disease.The pulmonary disease in patients with cystic fibrosis (CF) reflects genetic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that produce defective epithelial ion transport. The CF airway epithelial ion transport abnormalities lead to a well described pathophysiological cascade that adversely affects the innate defense Article, publication date, and citation information can be found at

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Abnormal ion content, hydration and granule expansion of the secretory granules from cystic fibrosis airway glandular cells

Cited by 20 publications

References 34 publications

Defective goblet cell exocytosis contributes to murine cystic fibrosis–associated intestinal disease

Defective goblet cell exocytosis contributes to murine cystic fibrosis–associated intestinal disease

Contribution of α7 nicotinic receptor to airway epithelium dysfunction under nicotine exposure

Pharmacological Properties ofN-(3,5-Diamino-6-chloropyrazine-2-carbonyl)-N′-4-[4-(2,3-dihydroxypropoxy)phenyl]butyl-guanidine Methanesulfonate (552-02), a Novel Epithelial Sodium Channel Blocker with Potential Clinical Efficacy for Cystic Fibrosis Lung Disease

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