The effect of NO-donors on chloride efflux, intracellular Ca2+ concentration and mRNA expression of CFTR and ENaC in cystic fibrosis airway epithelial cells

Oliynyk, Igor; Hussain, Rashida; Amin, Ahmad S.; Johannesson, Marie; Roomans, Godfried M.

doi:10.1016/j.yexmp.2013.03.003

Cited by 9 publications

(11 citation statements)

References 45 publications

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“…In any case, a sizeable increase in Cl − efflux after exposure to ambroxol occurs, which supports the functional efficacy of this drug at the cellular level. While there is a reasonable agreement between the data on Cl − efflux, CFTR mRNA and CFTR protein, there is no strict correlation between these parameters, probably because the relatioship between mRNA and protein/Cl − efflux is complex (Oliynyk et al, 2013). An important feature of CF is the abnormal balance between water efflux and influx.…”

Section: Discussionmentioning

confidence: 91%

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The effect of ambroxol on chloride transport, CFTR and ENaC in cystic fibrosis airway epithelial cells

Varelogianni

Hussain

Strid

et al. 2013

Cell Biology International

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Ambroxol, a mucokinetic anti-inflammatory drug, has been used for treatment of cystic fibrosis (CF). The respiratory epithelium is covered by the airway surface liquid (ASL), the thickness and composition of which is determined by Cl(-) efflux via the cystic fibrosis transmembrane conductance regulator (CFTR) and Na(+) influx via the epithelial Na(+) channel (ENaC). In cells expressing wt-CFTR, ambroxol increased the Cl(-) conductance, but not the bicarbonate conductance of the CFTR channels. We investigated whether treatment with ambroxol enhances chloride transport and/or CFTR and ENaC expression in CF airway epithelial cells (CFBE) cells. CFBE cells were treated with 100 µM ambroxol for 2, 4 or 8 h. mRNA expression for CFTR and ENaC subunits was analysed by real-time polymerase chain reaction (RT-PCR); protein expression was measured by Western blot. The effect of ambroxol on Cl(-) transport was measured by Cl(-) efflux measurements with a fluorescent chloride probe. Ambroxol significantly stimulated Cl(-) efflux from CFBE cells (a sixfold increase after 8 h treatment), and enhanced the expression of the mRNA of CFTR and α-ENaC, and of the CFTR protein. No significant difference was observed in β-ENaC after exposure to ambroxol, whereas mRNA expression of γ-ENaC was reduced. No significant effects of ambroxol on the ENaC subunits were observed by Western blot. Ambroxol did not significantly affect the intracellular Ca(2+) concentration. Upregulation of CFTR and enhanced Cl(-) efflux after ambroxol treatment should promote transepithelial ion and water transport, which may improve hydration of the mucus, and therefore be beneficial to CF-patients.

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Section: Discussionmentioning

confidence: 91%

“…While there is a reasonable agreement between the data on Cl − efflux, CFTR mRNA and CFTR protein, there is no strict correlation between these parameters, probably because the relatioship between mRNA and protein/Cl − efflux is complex (Oliynyk et al, 2013).…”

Section: Figure 3 Cftr Mrna Expression In Untreated Cfbe Cells (Contrmentioning

confidence: 89%

The effect of ambroxol on chloride transport, CFTR and ENaC in cystic fibrosis airway epithelial cells

Varelogianni

Hussain

Strid

et al. 2013

Cell Biology International

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“…The mechanism of action of GSNO is presumably that by S‐nitrosylation of the Hsp70/Hsp90 organizing protein (Hop) it promotes the expression of deltaF508‐CFTR at the cell surface (Marozkina et al, ). GSNO is not stable in vivo, and more stable alternatives have therefore been sought among other compounds that give off nitric oxide (NO) (Oliynyk et al, ). The action of GSNO is promoted by L‐cysteine (Servetnyk et al, ), and a mechanism for the action of GSNO and other NO‐donors could be that these compounds release NO extracellularly; NO binds to cystein and is taken up together with cystein by an amino acid transporter.…”

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confidence: 99%

“…The action of GSNO is promoted by L‐cysteine (Servetnyk et al, ), and a mechanism for the action of GSNO and other NO‐donors could be that these compounds release NO extracellularly; NO binds to cystein and is taken up together with cystein by an amino acid transporter. Inside the cell, cystein‐NO releases NO, which binds to the Hop protein, which it inactivates, and this inhibits the breakdown of delF508‐CFTR (Oliynyk et al, ). The mucolytic and antioxidant N‐acetylcysteine (NAC) (Varelogianni et al, ) not only increases the expression of CFTR in CF airway epithelial cells, but also the Cl − efflux from these cells, which may be related to the fact that it contains cysteine or to its antioxidant properties.…”

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confidence: 99%

Pharmacological treatment of the basic defect in cystic fibrosis

Roomans

2014

Cell Biology International

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Cystic fibrosis (CF) is a genetic disease due to a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel in epithelial cells. There are about 1900 mutations, divided in several groups, for example, stop mutations, mutations affecting the permeability of the channel, and mutations in which the mutated CFTR is recognized as abnormal and destroyed. Pharmacological treatment has become possible for stop mutations (about 10% of the patients), and for a rare mutation affecting channel permeability. For the majority of patients, however, that have a mutation in which the mutated CFTR is destroyed on its way to the cell membrane, research is still in progress, although a number of compounds have been identified that (at least partly) corrects the error in chloride transport.

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“…S-Nitrosoglutathione Reductase (GSNOR) regulates S-nitrosothiols and nitric oxide levels through catabolism of S-nitrosoglutathione 69. GSNOR inhibitors demonstrate anti-inflammatory, CFTR corrector,70,71 and potentiation activities. 72 GSNOR inhibitors may act through the Hsp70/Hsp90 organizing protein (Hop) pathway 73.…”

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confidence: 99%