scholarly journals Quercetin Increases Cystic Fibrosis Transmembrane Conductance Regulator–Mediated Chloride Transport and Ciliary Beat Frequency: Therapeutic Implications for Chronic Rhinosinusitis

2011 ◽  
Vol 25 (5) ◽  
pp. 307-312 ◽  
Author(s):  
Shaoyan Zhang ◽  
Nicholas Smith ◽  
Daniel Schuster ◽  
Christopher Azbell ◽  
Eric J. Sorscher ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Chronic Rhinosinusitis ◽  
Chloride Transport ◽  
Beat Frequency ◽  
Ciliary Beat Frequency ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Therapeutic Implications ◽  
Cystic Fibrosis Transmembrane ◽  
Ciliary Beat

Examining basal chloride transport using the nasal potential difference response in a murine model

2001 ◽  
Vol 281 (5) ◽  
pp. L1173-L1179 ◽  
Author(s):  
Kristine G. Brady ◽  
Thomas J. Kelley ◽  
Mitchell L. Drumm
Keyword(s):  
Cystic Fibrosis ◽  
Chloride Transport ◽  
Inbred Mice ◽  
Inbred Strains ◽  
Potential Difference ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Inbred Strains Of Mice ◽  
Cystic Fibrosis Transmembrane

Epithelia of humans and mice with cystic fibrosis are unable to secrete chloride in response to a chloride gradient or to cAMP-elevating agents. Bioelectrical properties measured using the nasal transepithelial potential difference (TEPD) assay are believed to reflect these cystic fibrosis transmembrane conductance regulator (CFTR)-dependent chloride transport defects. Although the response to forskolin is CFTR mediated, the mechanisms responsible for the response to a chloride gradient are unknown. TEPD measurements performed on inbred mice were used to compare the responses to low chloride and forskolin in vivo. Both responses show little correlation between or within inbred strains of mice, suggesting they are mediated through partially distinct mechanisms. In addition, these responses were assayed in the presence of several chloride channel inhibitors, including DIDS, diphenylamine-2-carboxylate, glibenclamide, and 5-nitro-2-(3-phenylpropylamino)-benzoic acid, and a protein kinase A inhibitor, the Rp diastereomer of adenosine 3′,5′-cyclic monophosphothioate ( Rp-cAMPS). The responses to low chloride and forskolin demonstrate significantly different pharmacological profiles to both DIDS and Rp-cAMPS, indicating that channels in addition to CFTR contribute to the low chloride response.

scholarly journals microRNA regulation of expression of the cystic fibrosis transmembrane conductance regulator gene

2011 ◽  
Vol 438 (1) ◽  
pp. 25-32 ◽  
Author(s):  
Austin E. Gillen ◽  
Nehal Gosalia ◽  
Shih-Hsing Leir ◽  
Ann Harris
Keyword(s):  
Cystic Fibrosis ◽  
Epithelial Cells ◽  
Cell Lines ◽  
Chloride Transport ◽  
Intestinal Cell ◽  
Transmembrane Conductance Regulator ◽  
Regulator Gene ◽  
Transmembrane Conductance ◽  
General Role ◽  
Cystic Fibrosis Transmembrane

The CFTR (cystic fibrosis transmembrane conductance regulator) gene shows a complex temporal and spatial pattern of expression that is controlled by multiple cis-acting elements interacting with the basal promoter. Although significant progress has been made towards understanding these genomic elements, there have been no reports of post-transcriptional regulation of CFTR by miRNAs (microRNAs). In the present study, we identify two miRNAs, hsa-miR-145 and hsa-miR-494, which regulate CFTR expression by directly targeting discrete sites in the CFTR 3′ UTR (untranslated region). We show that at least 12 miRNAs are capable of repressing endogenous CFTR mRNA expression in the Caco-2 cell line. Ten of these also inhibit expression of a reporter construct containing the CFTR 3′ UTR in one or more cell lines, and five repress endogenous CFTR protein expression in Caco-2 cells. Moreover, at least three are expressed in primary human airway epithelial cells, where CFTR expression is maintained at low levels in comparison with intestinal cell lines. Three of the miRNAs that target CFTR, hsa-miR-384, hsa-miR-494 and hsa-miR-1246, also inhibit expression of a reporter carrying the Na+–K+–Cl− co-transporter SLC12A2 [solute carrier family 12 (Na+–K+–Cl− transporters), member 2] 3′ UTR, suggesting that these miRNAs may play a more general role in regulating chloride transport in epithelial cells.

Cystic fibrosis transmembrane conductance regulator (CFTR) activity in nasal epithelial cells from cystic fibrosis patients with severe genotypes

2002 ◽  
Vol 103 (4) ◽  
pp. 417-424 ◽  
Author(s):  
C. ANDERSSON ◽  
A. DRAGOMIR ◽  
L. HJELTE ◽  
G.M. ROOMANS
Keyword(s):  
Cystic Fibrosis ◽  
Epithelial Cells ◽  
Chloride Transport ◽  
Essential Fatty Acids ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Mild Phenotype ◽  
Nasal Epithelial Cells ◽  
Function Number ◽  
Cystic Fibrosis Transmembrane

Cystic fibrosis is a heterogenic disease, in which the phenotype can also vary for patients with the same genotype. In the present study the function of the cystic fibrosis transmembrane conductance regulator (CFTR) in nasal epithelial cells from 19 adult patients with cystic fibrosis was investigated. All patients had severe mutations, whereby no or little functional CFTR is expected in the plasma membrane. Of the patients, 15 were homozygous for ΔF508-CFTR (i.e. CTFR lacking residue Phe-508). The others were ΔF508-heterozygous with 3659delC, 394delTT or 2183AA→G. Nasal epithelial cells, obtained by nasal brushings, were loaded with the fluorescent probe N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide to measure Cl- efflux. In most of the cystic fibrosis patients, forskolin plus isobutylmethylxanthine was unable to elicit any response. Unexpectedly, cells from three cystic fibrosis patients (two ΔF508/ΔF508 patients and one ΔF508/3659delC patient) responded to stimulation in a wild-type manner. It was investigated whether this residual chloride transport function was associated with a milder phenotype. Clinical parameters studied were lung function, number of antibiotic courses, Shwachman score, Bhalla score, age at chronic colonization with Pseudomonas aeruginosa and the pattern of essential fatty acids in serum phospholipids. Unknown factors may affect the presence of functional CFTR in patients with severe CFTR mutations. However, we could not find a correlation between the response to cAMP and any of the phenotype parameters. It appears that functional cAMP transport in the nasal epithelium is no guarantee of a mild phenotype and, conversely, that a patient lacking cAMP-dependent chloride transport can develop a mild phenotype.

scholarly journals Lumacaftor and Matrine: Possible Therapeutic Combination to Counteract the Inflammatory Process in Cystic Fibrosis

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 422
Author(s):  
Michela Pecoraro ◽  
Silvia Franceschelli ◽  
Maria Pascale
Keyword(s):  
Cystic Fibrosis ◽  
Inflammatory Process ◽  
Chloride Transport ◽  
Electrolyte Imbalance ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Δf508 Cftr ◽  
Cftr Protein ◽  
Cell Cytosol ◽  
Cystic Fibrosis Transmembrane

Cystic fibrosis is a monogenic, autosomal, recessive disease characterized by an alteration of chloride transport caused by mutations in the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene. The loss of Phe residue in position 508 (ΔF508-CFTR) causes an incorrect folding of the protein causing its degradation and electrolyte imbalance. CF patients are extremely predisposed to the development of a chronic inflammatory process of the bronchopulmonary system. When the cells of a tissue are damaged, the immune cells are activated and trigger the production of free radicals, provoking an inflammatory process. In addition to routine therapies, today drugs called correctors are available for mutations such as ΔF508-CFTR as well as for others less frequent ones. These active molecules are supposed to facilitate the maturation of the mutant CFTR protein, allowing it to reach the apical membrane of the epithelial cell. Matrine induces ΔF508-CFTR release from the endoplasmic reticulum to cell cytosol and its localization on the cell membrane. We now have evidence that Matrine and Lumacaftor not only restore the transport of mutant CFTR protein, but probably also counteract the inflammatory process by improving the course of the disease.

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