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Chloride transport and inflammation in cystic fibrosis airways
Örebro University, School of Health and Medical Sciences.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cystic fibrosis (CF) is one of the most common lethal, autosomal recessive inherited diseases among Caucasians. It is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel activated by cyclic AMP. The disturbed electrolyte transport caused by the impaired CFTR channel leads to defective mucociliary clearance, airway obstruction and chronic airway infections.

Three different substances (N-acetylcysteine, duramycin and ambroxol) were tested in order to investigate if they could improve Cl- transport across epithelia and if so, through which mechanisms.

N-acetylcysteine (NAC), a well-known mucolytic and anti-oxidant drug increased significantly Cl-efflux from cystic fibrosis bronchial epithelial (CFBE) cells. It was shown that NAC can (partially) correct the Cl- transport deficiency in CF airway epithelial cells withF508-CFTR through a direct effect on CFTR (Paper I).

Duramycin increased Cl- efflux from CF airway epithelial cell in a very narrow concentration range. That effect is not associated with an increase in the intracellular calcium concentration (Paper II). The fact that results of a clinical study of duramycin, carried out several years ago, have not been published suggests that duramycin is not only ineffective in vitro, but also in vivo.

Ambroxol has been widely used as supplementary therapy for the treatment of many respiratory diseases. It was shown that 8h treatment with ambroxol caused a nearly six-fold increase of Cl- efflux from CF airway epithelial cells, which brings the Cl- efflux up to the level of cells with wild-type CFTR (Paper III).

Moreover, we studied the role of the innate immunity system in CF airway epithelial cells. High levels of Nod1 were found both in CF and non-CF airway epithelial cells, but a decreased expression of Nod2, and decreased levels of the pro-inflammatory cytokines IL-6 and IL-8 were found in CF airway epithelial cells compared to non-CF cells. The decreased levels of Nod2 suggest that the CF-cells are less able to recognize pathogens such as Pseudomonas aeruginosa, which might lead to a higher uptake of the pathogen (Paper IV).

Place, publisher, year, edition, pages
Örebro: Örebro universitet , 2011. , p. 65
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 62
Keywords [en]
Cystic fibrosis, CFTR, chloride efflux, N-acetylcysteine, ambroxol, duramycin, Nod-like receptors, cytokines
National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
URN: urn:nbn:se:oru:diva-19126ISBN: 978-91-7668-830-4 (print)OAI: oai:DiVA.org:oru-19126DiVA, id: diva2:445446
Public defence
2011-11-25, Seminarierum Berguven (F1), Universitetssjukhuset, Örebro, 13:00 (English)
Opponent
Supervisors
Available from: 2011-10-04 Created: 2011-10-04 Last updated: 2017-10-17Bibliographically approved
List of papers
1. The effect of N-acetylcysteine on chloride efflux from airway epithelial cells
Open this publication in new window or tab >>The effect of N-acetylcysteine on chloride efflux from airway epithelial cells
2010 (English)In: Cell Biology International, ISSN 1065-6995, E-ISSN 1095-8355, Vol. 34, no 3, p. 245-252Article in journal (Refereed) Published
Abstract [en]

Defective chloride transport in epithelial cells increases mucus viscosity and leads to recurrent infections with high oxidative stress in patients with CF (cystic fibrosis). NAC (N-acetylcysteine) is a well known mucolytic and antioxidant drug, and an indirect precursor of glutathione. Since GSNO (S-nitrosoglutathione) previously has been shown to be able to promote Cl efflux from CF airway epithelial cells, it was investigated whether NAC also could stimulate Cl efflux from CF and non-CF epithelial cells and through which mechanisms. CFBE (CF bronchial epithelial cells) and normal bronchial epithelial cells (16HBE) were treated with 1 mM, 5 mM, 10 mM or 15 mM NAC for 4 h at 37°C. The effect of NAC on Cl transport was measured by Cl efflux measurements and by X-ray microanalysis. Cl efflux from CFBE cells was stimulated by NAC in a dose-dependent manner, with 10 mM NAC causing a significant increase in Cl efflux with nearly 80% in CFBE cells. The intracellular Cl concentration in CFBE cells was significantly decreased up to 60% after 4 h treatment with 10 mM NAC. Moreover immunocytochemistry and Western blot experiments revealed expression of CFTR channel on CFBE cells after treatment with 10 mM NAC. The stimulation of Cl efflux by NAC in CF airway epithelial cells may improve hydration of the mucus and thereby be beneficial for CF patients.

Place, publisher, year, edition, pages
London: Portland Press Ltd, 2010
Keywords
airway epithelium, chloride transport, cystic fibrosis, N-acetylcysteine, Medical cell biology, Morphology, cell biology, pathology
National Category
Cell and Molecular Biology Medical and Health Sciences Cell and Molecular Biology
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-12451 (URN)10.1042/CBI20090007 (DOI)000277391600002 ()
Note

Georgia Varelogianni, Igor Oliynyk, Godfried M Roomans are also affiliated w. Department of Medical Cell Biology, Uppsala University, Box 571, SE-75123 Uppsala, Sweden

Available from: 2010-11-12 Created: 2010-11-12 Last updated: 2018-04-19Bibliographically approved
2. Effect of duramycin on chloride transport and intracellular calcium concentration in cystic fibrosis and non-cystic fibrosis epithelia
Open this publication in new window or tab >>Effect of duramycin on chloride transport and intracellular calcium concentration in cystic fibrosis and non-cystic fibrosis epithelia
2010 (English)In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 118, no 12, p. 982-990Article in journal (Refereed) Published
Abstract [en]

The lantibiotic duramycin (Moli1901, Lancovutide) has been suggested as a drug of choice in the treatment for cystic fibrosis (CF). It has been proposed that duramycin may stimulate chloride secretion through Ca2+-activated Cl channels (CaCC). We investigated whether duramycin exhibited any effect on Cl efflux and intracellular Ca2+ concentration ([Ca2+]i) in CF and non-CF epithelial cells. Duramycin did stimulate Cl efflux from CF bronchial epithelial cells (CFBE) in a narrow concentration range (around 1 μM). However, 100 and 250 μM of duramycin inhibited Cl efflux from CFBE cells. An inhibitor of the CF transmembrane conductance regulator (CFTRinh-172) and a blocker of the capacitative Ca2+ entry, gadolinium chloride, inhibited the duramycin-induced Cl efflux. No effect on Cl efflux was observed in non-CF human bronchial epithelial cells (16HBE), human airway submucosal gland cell line, human pancreatic epithelial cells, CF airway submucosal gland epithelial cells, and CF pancreatic cells. The [Ca2+]i was increased by 3 μM duramycin in 16HBE cells, but decreased after 1, and 3 μM of duramycin in CFBE cells. The results suggest that the mechanism responsible for the stimulation of Cl efflux by duramycin is mainly related to unspecific changes of the cell membrane or its components rather than to effects on CaCC.

Place, publisher, year, edition, pages
New York, USA: John Wiley & Sons, 2010
Keywords
Duramycin, cystic fibrosis, airway epithelium, chloride efflux
National Category
Medical and Health Sciences Immunology
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-12442 (URN)10.1111/j.1600-0463.2010.02680.x (DOI)000284317500010 ()21091780 (PubMedID)2-s2.0-78649506897 (Scopus ID)
Available from: 2010-11-11 Created: 2010-11-11 Last updated: 2018-04-19Bibliographically approved
3. The effect of ambroxol on chloride transport and mRNA expression of CFTR and ENaC in cystic fibrosis airway epithelial cells
Open this publication in new window or tab >>The effect of ambroxol on chloride transport and mRNA expression of CFTR and ENaC in cystic fibrosis airway epithelial cells
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-20478 (URN)
Available from: 2011-12-05 Created: 2011-12-05 Last updated: 2017-10-17Bibliographically approved
4. Decreased expression of Nod2-receptors and production of pro-inflammatory cytokines in cystic fibrosis airway epithelial cells
Open this publication in new window or tab >>Decreased expression of Nod2-receptors and production of pro-inflammatory cytokines in cystic fibrosis airway epithelial cells
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-20479 (URN)
Available from: 2011-12-05 Created: 2011-12-05 Last updated: 2017-10-17Bibliographically approved

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