Extracellular Alkalinization Stimulates Calcium-activated Chloride Conductance in Cystic Fibrosis Human Airway Epithelial Cells

Dankó, Titanilla; Hargitai, Dóra; Pataki, Ágnes; Hakim, Hasif; Molnár, Miklós; Zsembery, Ákos

doi:10.1159/000327967

Cited by 5 publications

(2 citation statements)

References 40 publications

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“…The possible regulation of CFTR activity by pHe, on the other hand, has been controversial (Reddy et al, 1998;Sherry et al, 1994). The pHe also regulates other Cl-channels; for example, extracellular alkalinization stimulates calcium-activated chloride channels (CaCCs) in CF-cells (IB3-1) (Danko et al, 2011), which are an alternative way to increase Cl-transport in these cells (Schwiebert et al, 1998).…”

Section: Cftr and Asl Phmentioning

confidence: 99%

Extracellular pH and lung infections in cystic fibrosis

Massip-Copiz

Santa‐Coloma

2018

European Journal of Cell Biology

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Cystic fibrosis (CF) is an autosomal recessive disease caused by CFTR mutations. It is characterized by high NaCl concentration in sweat and the production of a thick and sticky mucus, occluding secretory ducts, intestine and airways, accompanied by chronic inflammation and infections of the lungs. This causes a progressive and lethal decline in lung function. Therefore, finding the mechanisms driving the high susceptibility to lung infections has been a key issue. For decades the prevalent hypothesis was that a reduced airway surface liquid (ASL) volume and composition, and the consequent increased mucus concentration (dehydration), create an environment favoring infections. However, a few years ago, in a pig model of CF, the Na/K concentrations and the ASL volume were found intact. Immediately a different hypothesis arose, postulating a reduced ASL pH as the cause for the increased susceptibility to infections, due to a diminished bicarbonate secretion through CFTR. Noteworthy, a recent report found normal ASL pH values in CF children and in cultured primary airway cells, challenging the ASL pH hypothesis. On the other hand, recent evidences revitalized the hypothesis of a reduced ASL secretion. Thus, the role of the ASL pH in the CF is still a controversial matter. In this review we discuss the basis that sustain the role of CFTR in modulating the extracellular pH, and the recent results sustaining the different points of view. Finding the mechanisms of CFTR signaling that determine the susceptibility to infections is crucial to understand the pathophysiology of CF and related lung diseases.

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Section: Cftr and Asl Phmentioning

confidence: 99%

Extracellular pH and lung infections in cystic fibrosis

Massip-Copiz

Santa‐Coloma

2018

European Journal of Cell Biology

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“…While Cl − (and hence, water) efflux in the human airways is mainly under the control of CFTR, Na þ (and water) influx is controlled by the epithelial sodium channel (ENaC) in a way that is unclear (Bachhuber et al, 2005;Reddy and Quinton, 2005;Joo et al, 2006;Stanke et al, 2006;Collawn et al, 2012). A minor part of Cl − efflux may occur via Ca 2þ -activated Cl − channels (Roomans, 2003;Dankó et al, 2011). Not only the dysfunctional CFTR channel, but also an inadequacy in CFTR-ENaC coupling, contributes to disturbed electrolyte transport across the membrane (Berdiev et al, 2009), although this notion is disputed (Collawn et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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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Sex differences in the inflammatory mediator-induced sensitization of dural afferents

Scheff

Gold

2011

Journal of Neurophysiology

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Scheff NN, Gold MS. Sex differences in the inflammatory mediatorinduced sensitization of dural afferents. J Neurophysiol 106: 1662-1668, 2011. First published July 13, 2011 doi:10.1152 doi:10. /jn.00196.2011 of the adult population suffers from migraine. This debilitating pain disorder is three times more prevalent in women than in men. To begin to evaluate the underlying mechanisms that may contribute to this sex difference, we tested the hypothesis that there is a sex difference in the inflammatory mediator (IM)-induced sensitization of dural afferents. Acutely dissociated retrogradely labeled dural afferents from adult Sprague-Dawley rats were examined with whole cell patchclamp recordings. Baseline passive and active electrophysiological properties of dural afferents from both sexes were comparable. However, while IM-induced increases in the excitability of dural afferents from male and female rats were also comparable, the proportion of dural afferents from female rats sensitized by IM (ϳ100%) was significantly greater than that of dural afferents from male rats (ϳ50%). This appeared to be due to differences downstream of IM receptors, as tetrodotoxinresistant sodium current was increased by IM in a majority of male dural afferents (13/14). These data indicate that there are both quantitative and qualitative differences in the IM-induced sensitization of dural afferents that may contribute to the sex difference in the manifestation of migraine.trigeminal ganglion neuron; current clamp; primary afferent; chloride current; pain CONSERVATIVE ESTIMATES INDICATE that over 20% of the adult population suffers from migraine. Interestingly, this debilitating pain disorder is far more common in women than in men, with a prevalence roughly three times higher in women than in men [18% vs. 6% (Stewart et al. 1992)] and an incidence more than two times higher [43% vs. 18% (Stewart et al. 2008)]. The underlying mechanisms of this sex difference have yet to be identified.While there is still debate over the mechanisms underlying the initiation of a migraine attack, compelling evidence indicates that activation of primary afferents innervating the dural vasculature mediates migraine pain. Electrical stimulation of the dura and associated vasculature is associated with mi-

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Extracellular Alkalinization Stimulates Calcium-activated Chloride Conductance in Cystic Fibrosis Human Airway Epithelial Cells

Cited by 5 publications

References 40 publications

Extracellular pH and lung infections in cystic fibrosis

Extracellular pH and lung infections in cystic fibrosis

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

Sex differences in the inflammatory mediator-induced sensitization of dural afferents

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