Cellular Cl- transport in cultured cystic fibrosis airway epithelium

Willumsen, Niels J.; Davis, C. William; Boucher, Richard C.

doi:10.1152/ajpcell.1989.256.5.c1045

Cited by 68 publications

(49 citation statements)

References 10 publications

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“…These data suggest that when K 1 efflux through the Nys pores is prevented by elevation of the luminal [K 1 ], the absolute magnitude of net Na 1 influx is revealed. As previously reported, elevation of the extracellular [K 1 ] did not affect HBE bioelectrics in the absence of Nys (20).…”

Section: Resultssupporting

confidence: 83%

Modelling Dysregulated Na⁺ Absorption in Airway Epithelial Cells with Mucosal Nystatin Treatment

Livraghi

Mall

Paradiso³

et al. 2008

Am J Respir Cell Mol Biol

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In cystic fibrosis (CF), the absence of functional CFTR leads to dysregulated Na 1 absorption across airway epithelia. We established an in vitro model of dysregulated Na 1 absorption by treating polarized normal human bronchial epithelial cells (HBEs) with nystatin (Nys), a polyene antibiotic that enables monovalent cations to permeate biological membranes. Acute mucosal Nys produced a rapid increase in short circuit current (I sc ) that reflected increased transepithelial Na 1 absorption and required Na 1 /K 1 ATPase activity. The acute increase in I sc was associated with increased mucosal liquid absorption. Prolonged mucosal Nys treatment resulted in sustained Na 1 hyperabsorption, associated with increased mucosal liquid absorption in comparison with naïve (nontreated, kept under airliquid interface conditions) or vehicle-treated cultures. Nys treatment was not toxic. Increased lactate accumulation in Nys-treated culture media suggested a higher metabolic rate associated with the higher energy demand for Na 1 transport. After chronic Nys treatment, the increased I sc was rapidly lost when the cultures were mounted in Ussing chambers, indicating that Nys could be rapidly removed from the apical membrane. Importantly, chronic Nys treatment promoted sustained mucosal liquid depletion and caused mucus dehydration, compaction, and adhesion to the apical surface of Nys-treated cultures. We conclude that mucosal Nys treatment of HBEs provides a simple in vitro model to recapitulate the Na 1 and volume hyperabsorptive features of CF airway epithelia.

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Section: Resultssupporting

confidence: 83%

Modelling Dysregulated Na⁺ Absorption in Airway Epithelial Cells with Mucosal Nystatin Treatment

Livraghi

Mall

Paradiso³

et al. 2008

Am J Respir Cell Mol Biol

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“…The same technique revealed the absence of Cl -secretion under conditions when ENaC was blocked with amiloride under basal or b-agonist-stimulated conditions. Subsequent double-barrelled microelectrode studies of freshly excised and cultured normal and CF cells detected a raised apical membrane Na z conductance in CF cells and a reduced or absent Cl -conductance [58][59][60][61]. Ultimately, studies of the apical membrane channels with patch clamp techniques revealed an increased activity of ENaC (increased open probability) in CF compared with normal cells [62].…”

Section: The Cell Biology Of Cystic Fibrosismentioning

confidence: 99%

New concepts of the pathogenesis of cystic fibrosis lung disease

Rc¹

2003

Eur Respir J

575

406

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Although there has been impressive progress in the elucidation of the genetic and molecular basis of cystic fibrosis (CF), the pathogenesis of CF lung disease remains obscure. The elucidation of the pathogenesis of CF lung disease requires both a full description of normal innate airway defence and how absent function of the cystic fibrosis transmembrane regulator protein (CFTR) adversely perturbs this activity.Recent data have linked the abnormal ion transport properties of CF airway epithelia to depleted airway surface liquid (ASL) volume, reflecting the combined defects of accelerated Na+transport and the failure to secrete Cl−. Depletion of a specific compartment of the ASL,i.e.the periciliary liquid (PCL), appears to abrogate both cilia-dependent and cough clearance.Subsequent to PCL depletion, mucus adheres to airway surfaces and persistent mucin secretion generates the formation of “thickened” mucus plaques and plugs, which become the nidus for bacterial infection. The paucity of liquid in these plaques/plugs, and the hypoxia in this environment, appear to promote biofilm bacterial infection.Therapeutic agents that restore airway surface liquid volume,i.e.blockers of Na+transport, initiators of Cl−transport and osmolytes, are reviewed, as are strategies that may be required to use volume-restoring agents safely in patients with cystic fibrosis.

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“…Cultures of CF nasal epithelium (n ϭ 8, triplicate preparations) were mounted in a modified Ussing chamber. The CF apical membrane ionic conductance is virtually zero in the presence of luminal amiloride (10 Ϫ4 M), because CFTR is absent and Na ϩ channels are blocked (19), and basal calcium activated chloride conductance is minimal in the absence of a signal for increased intracellular Ca 2ϩ (20). Consequently, voltage changes induced by changes in apical vs. basolateral anion bath concentrations are likely dominated by bi-ionic PDs across the paracellular shunt (21).…”

Section: Assessment Of Paracellular Hcomentioning

confidence: 99%

Abnormal surface liquid pH regulation by cultured cystic fibrosis bronchial epithelium

Coakley

Grubb

Paradiso

et al. 2003

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

269

302

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Cystic fibrosis (CF) transmembrane conductance regulator (CFTR)-dependent airway epithelial bicarbonate transport is hypothesized to participate in airway surface liquid pH regulation and contribute to lung defense. We measured pH and ionic composition in apical surface liquid (ASL) on polarized normal (NL) and CF primary bronchial epithelial cell cultures under basal conditions, after cAMP stimulation, and after challenge with luminal acid loads. Under basal conditions, CF epithelia acidified ASL more rapidly than NL epithelia. Two ASL pH regulatory paths that contributed to basal pH were identified in the apical membrane of airway epithelia, and their activities were measured. We detected a ouabain-sensitive (nongastric) H ؉ ,K ؉ -ATPase that acidified ASL, but its activity was not different in NL and CF cultures. We also detected the following evidence for a CFTR-dependent HCO 3 ؊ secretory pathway that was defective in CF: (i) ASL [HCO 3 ؊ ] was higher in NL than CF ASL; (ii) activating CFTR with forskolin͞3-isobutyl-1-methylxanthine alkalinized NL ASL but acidified CF ASL; and (iii) NL airway epithelia more rapidly and effectively alkalinized ASL in response to a luminal acid challenge than CF epithelia. We conclude that cultured human CF bronchial epithelial pH ASL is abnormally regulated under basal conditions because of absent CFTRdependent HCO 3 ؊ secretion and that this defect can lead to an impaired capacity to respond to airway conditions associated with acidification of ASL.

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Cellular Cl- transport in cultured cystic fibrosis airway epithelium

Cited by 68 publications

References 10 publications

Modelling Dysregulated Na⁺ Absorption in Airway Epithelial Cells with Mucosal Nystatin Treatment

Modelling Dysregulated Na⁺ Absorption in Airway Epithelial Cells with Mucosal Nystatin Treatment

New concepts of the pathogenesis of cystic fibrosis lung disease

Abnormal surface liquid pH regulation by cultured cystic fibrosis bronchial epithelium

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Cellular Cl- transport in cultured cystic fibrosis airway epithelium

Cited by 68 publications

References 10 publications

Modelling Dysregulated Na+ Absorption in Airway Epithelial Cells with Mucosal Nystatin Treatment

Modelling Dysregulated Na+ Absorption in Airway Epithelial Cells with Mucosal Nystatin Treatment

New concepts of the pathogenesis of cystic fibrosis lung disease

Abnormal surface liquid pH regulation by cultured cystic fibrosis bronchial epithelium

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Modelling Dysregulated Na⁺ Absorption in Airway Epithelial Cells with Mucosal Nystatin Treatment

Modelling Dysregulated Na⁺ Absorption in Airway Epithelial Cells with Mucosal Nystatin Treatment