CFTR Delivery to 25% of Surface Epithelial Cells Restores Normal Rates of Mucus Transport to Human Cystic Fibrosis Airway Epithelium

Zhang, Liqun; Button, Brian; Gabriel, Sherif E.; Burkett, Susan E.; Yu, Yang; Skiadopoulos, Mario H.; Dang, Yan L.; Vogel, Leatrice; McKay, Tristan R.; Mengos, April; Boucher, Richard C.; Collins, Peter L.; Pickles, Raymond J.

doi:10.1371/journal.pbio.1000155

Cited by 174 publications

(159 citation statements)

References 57 publications

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“…2B). These data are consistent with results from human airway epithelia expressing either endogenous levels of CFTR or overexpressing CFTR (10)(11)(12)(13)(14). However, as the percentage of WT cells increased, Airway epithelia were generated with varying ratios of CFTR ΔF508/ΔF508 and CFTR +/+ cells.…”

Section: Hcosupporting

confidence: 87%

“…In contrast, a different study reported that CFTR expression in all of the cells reduced ΔIsc (amiloride) , but there was no relationship to vector dose (44). Between those extremes, one study reported that, as the percentage of transduced cells increased (∼60% was the highest percentage tested), ΔIsc (amiloride) progressively decreased (12). Another study reported variable effects of CFTR expression on basal transepithelial voltage in CF xenografts (11).…”

Section: Hcomentioning

confidence: 99%

“…n = 7-8. The * indicates the difference from epithelia with 100% WT cells by repeated measures ANOVA, P < 0.05. epithelium are WT or overexpress CFTR, Cl − secretion rises to the level of WT epithelia (10)(11)(12)(13)(14). However, knowledge that CFTR conducts HCO 3 − (48), that HCO 3 − is the major pH buffer of ASL (49), and that HCO 3 − secretion plays a key role in airway host defense (31)(32)(33)(34)(35)50) led us to test the relationship between CFTR expression and HCO 3 − secretion.…”

Section: Increasing Cftr Expression Progressively Enhances Asl Host Dmentioning

confidence: 99%

“…They found that CFTR expression in ∼7% of cells generated changes in transepithelial voltage, in the presence of a Cl − concentration gradient, that were ∼75% of voltage changes in non-CF xenografts. Zhang et al (12) used a parainfluenza virus to overexpress CFTR in cultured human CF airway epithelia. ΔIsc (cAMP) progressively increased as the percentage of transduced epithelial cells increased.…”

mentioning

confidence: 99%

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Relationships among CFTR expression, HCO ₃ ⁻ secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies

Shah

Ernst

Tang

et al. 2016

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

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Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. Airway disease is the major source of morbidity and mortality. Successful implementation of gene- and cell-based therapies for CF airway disease requires knowledge of relationships among percentages of targeted cells, levels of CFTR expression, correction of electrolyte transport, and rescue of host defense defects. Previous studies suggested that, when ∼10–50% of airway epithelial cells expressed CFTR, they generated nearly wild-type levels of Cl− secretion; overexpressing CFTR offered no advantage compared with endogenous expression levels. However, recent discoveries focused attention on CFTR-mediated HCO3− secretion and airway surface liquid (ASL) pH as critical for host defense and CF pathogenesis. Therefore, we generated porcine airway epithelia with varying ratios of CF and wild-type cells. Epithelia with a 50:50 mix secreted HCO3− at half the rate of wild-type epithelia. Likewise, heterozygous epithelia (CFTR+/− or CFTR+/∆F508) expressed CFTR and secreted HCO3− at ∼50% of wild-type values. ASL pH, antimicrobial activity, and viscosity showed similar relationships to the amount of CFTR. Overexpressing CFTR increased HCO3− secretion to rates greater than wild type, but ASL pH did not exceed wild-type values. Thus, in contrast to Cl− secretion, the amount of CFTR is rate-limiting for HCO3− secretion and for correcting host defense abnormalities. In addition, overexpressing CFTR might produce a greater benefit than expressing CFTR at wild-type levels when targeting small fractions of cells. These findings may also explain the risk of airway disease in CF carriers.

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Section: Hcosupporting

confidence: 87%

Section: Hcomentioning

confidence: 99%

Section: Increasing Cftr Expression Progressively Enhances Asl Host Dmentioning

confidence: 99%

mentioning

confidence: 99%

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Relationships among CFTR expression, HCO ₃ ⁻ secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies

Shah

Ernst

Tang

et al. 2016

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

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“…The osmotic potential exerted by CF mucus (.8% solids), but not healthy mucus (;2% solids), was demonstrated to be sufficient to dehydrate the PCL and collapse cilia (52), and to restrict mobility of bacteria and foster formation of bacterial biofilm precursor macrocolonies (53). Restoration of CFTR expression in CF primary epithelial cells by viral transduction significantly increases ASL depth, ciliary beat frequency, and mucus transport, supporting the idea that loss of CFTR function mediates ASL dehydration (54). Therefore, the bulk of available evidence links reduced ASL volume to increased propensity for infection, with reduced CFTR ion transport leading to reduced mucin hydration in the mucus layer followed by PCL dehydration, ciliary collapse, mucostasis, and bacterial colonization.…”

mentioning

confidence: 66%

Inhibitors of pendrin anion exchange identified in a small molecule screen increase airway surface liquid volume in cystic fibrosis

Haggie

Phuan²,

Tan³

et al. 2016

FASEB j.

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Pendrin (SLC26A4) is a Cl 2 /anion exchanger expressed in the epithelium of inflamed airways where it is thought to facilitate Cl 2 absorption and HCO 3 2 secretion. Studies using pendrin knockout mice and airway epithelial cells from hearing-impaired subjects with pendrin loss of function suggest involvement of pendrin in inflammatory lung diseases, including cystic fibrosis (CF), perhaps by regulation of airway surface liquid (ASL) volume. Here we identified small-molecule pendrin inhibitors and demonstrated their efficacy in increasing ASL volume. A cell-based, functional high-throughput screen of ∼36,000 synthetic small molecules produced 3 chemical classes of inhibitors of human pendrin. After structure-activity studies, tetrahydropyrazolopyridine and pyrazolothiophenesulfonamide compounds reversibly inhibited pendrin-facilitated Cl 2 exchange with SCN 2 , I 2 , NO 3 2 , and HCO 3 2 with drug concentration causing 50% inhibition down to ∼2.5 mM. In well-differentiated primary cultures of human airway epithelial cells from non-CF and CF subjects, treatment with IL-13, which causes inflammation with strong pendrin up-regulation, strongly increased Cl 2 /HCO 3 2 exchange and the increase was blocked by pendrin inhibition. Pendrin inhibition significantly increased ASL depth (by ∼8 mm) in IL-13-treated non-CF and CF cells but not in untreated cells. These studies implicate the involvement of pendrin-facilitated Cl 2 / HCO 3 2 in the regulation of ASL volume and suggest the utility of pendrin inhibitors in inflammatory lung diseases, including CF

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Nebuliser systems for drug delivery in cystic fibrosis

Daniels

Mills

Whitaker

2013

Cochrane Database of Systematic Reviews

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Clinicians should be aware of the variability in the performance of different nebuliser systems. Technologies such as adaptive aerosol delivery and vibrating mesh technology have advantages over conventional systems in terms of treatment time, deposition as a percentage of priming dose, patient preference and adherence. There is a need for long-term randomised controlled trials of these technologies to determine patient-focused outcomes (such as quality of life and burden of care), safe and effective dosing levels of medications and clinical outcomes (such as hospitalisations and need for antibiotics) and an economic evaluation of their use.

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CFTR Delivery to 25% of Surface Epithelial Cells Restores Normal Rates of Mucus Transport to Human Cystic Fibrosis Airway Epithelium

Abstract: Delivering CFTR to ciliated cells of cystic fibrosis (CF) patients fully restores ion and fluid transport to the lumenal surface of airway epithelium and returns mucus transport rates to those of non-CF airways.

Cited by 174 publications

References 57 publications

Relationships among CFTR expression, HCO ₃ ⁻ secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies

Relationships among CFTR expression, HCO ₃ ⁻ secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies

Inhibitors of pendrin anion exchange identified in a small molecule screen increase airway surface liquid volume in cystic fibrosis

Nebuliser systems for drug delivery in cystic fibrosis

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CFTR Delivery to 25% of Surface Epithelial Cells Restores Normal Rates of Mucus Transport to Human Cystic Fibrosis Airway Epithelium

Abstract: Delivering CFTR to ciliated cells of cystic fibrosis (CF) patients fully restores ion and fluid transport to the lumenal surface of airway epithelium and returns mucus transport rates to those of non-CF airways.

Cited by 174 publications

References 57 publications

Relationships among CFTR expression, HCO 3 − secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies

Relationships among CFTR expression, HCO 3 − secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies

Inhibitors of pendrin anion exchange identified in a small molecule screen increase airway surface liquid volume in cystic fibrosis

Nebuliser systems for drug delivery in cystic fibrosis

Contact Info

Product

Resources

About

Relationships among CFTR expression, HCO ₃ ⁻ secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies

Relationships among CFTR expression, HCO ₃ ⁻ secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies