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  • 1.
    Hussain, Shahida
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. IRiSC-Inflammatory Response and Infection Susceptibility Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Varelogianni, Georgia
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Särndahl, Eva
    Örebro University, School of Medicine, Örebro University, Sweden. IRiSC-Inflammatory Response and Infection Susceptibility Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Roomans, Godfried M
    Örebro University, School of Medicine, Örebro University, Sweden. IRiSC-Inflammatory Response and Infection Susceptibility Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    N-acetylcysteine and azithromycin affect the innate immune response in cystic fibrosis bronchial epithelial cells in vitro2015In: Experimental Lung Research, ISSN 0190-2148, E-ISSN 1521-0499, Vol. 41, no 5, p. 251-260Article in journal (Refereed)
    Abstract [en]

    Background and objective: We have previously reported that N-acetylcysteine (NAC), ambroxol and azithromycin (AZM) (partially) correct the chloride efflux dysfunction in cystic fibrosis bronchial epithelial (CFBE) cells with the ΔF508 homozygous mutation in vitro.

    Methods: In the present paper, we further investigated possible immunomodulatory effects of these drugs on the regulation of the innate immune system by studying the expression of the cytosolic NOD-like receptors NLRC1 and NLRC2, and interleukin (IL)-6 production in CFBE cells.

    Results: Under basal conditions, PCR and Western Blot data indicate that the NLRC2 receptor has a reduced expression in CF cells as compared to non-CF (16HBE) cells, but that the NLRC1 expression is the same in both cell lines. AZM significantly upregulated NLRC1 and NLRC2 while NAC upregulated only NLRC2 receptor expression in CF cells. Reduced basal IL-6 production was found in CF cells as compared to non-CF cells. MDP (an NLRC2 agonist), NAC and AZM, but not Tri-DAP (an NLRC1 agonist), increased IL-6 production in CF cells, indicating that in CF cells IL-6 upregulation is independent of NLRC1, but involves the activation of NLRC2.

    Conclusion: Overall, the results indicate that NAC and AZM not only can correct the chloride efflux dysfunction but also have a weakly strengthening effect on the innate immune system.

  • 2.
    Oliynyk, Igor
    et al.
    Örebro University, School of Health and Medical Sciences. Örebro University Hospital, Örebro, Sweden; Dept Med Cell Biol, Uppsala Univ, Uppsala, Sweden.
    Varelogianni, Georgia
    Örebro University, School of Health and Medical Sciences. Örebro University Hospital, Örebro, Sweden; Dept Med Cell Biol, Uppsala Univ, Uppsala, Sweden.
    Roomans, Godfried M.
    Örebro University, School of Health and Medical Sciences. Örebro University Hospital, Örebro, Sweden.
    Johannesson, Marie
    Örebro University Hospital, Örebro , Sweden; Department of Paediatrics and Child Health, University of Otago, Wellington Campus, Wellington, New Zealand.
    Effect of duramycin on chloride transport and intracellular calcium concentration in cystic fibrosis and non-cystic fibrosis epithelia2010In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 118, no 12, p. 982-990Article in journal (Refereed)
    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.

  • 3.
    Oliynyk, Igor
    et al.
    Örebro University, School of Health and Medical Sciences.
    Varelogianni, Georgia
    Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
    Schalling, Martin
    Department of Molecular Medicine and Surgery, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden.
    Stenkvist Asplund, Monika
    Department of Otorhinolaryngology, Uppsala University Hospital, Uppsala, Sweden.
    Roomans, Godfried M.
    Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
    Johannesson, Marie
    Uppsala CF Center, Uppsala University Hospital, Uppsala, Sweden.
    Azithromycin increases chloride efflux from cystic fibrosis airway epithelial cells2009In: Experimental Lung Research, ISSN 0190-2148, E-ISSN 1521-0499, Vol. 35, no 3, p. 210-221Article in journal (Refereed)
    Abstract [en]

    It was investigated whether azithromycin (AZM) stimulates chloride (Cl−) efflux from cystic fibrosis (CF) and non-CF airway epithelial cells, possibly secondary to up-regulation of the multidrug resistance protein (MDR). CF and non-CF human airway epithelial cell lines (CFBE and 16HBE) were treated with 0.4, 4, and 40 μ g/mL AZM for 4 days. Cl− efflux was explored in the presence or absence of specific inhibitors of CFTR and alternative Cl−  channels. Six CF patients received AZM (500 mg daily) for 6 months. The percentage of predicted forced vital capacity (FVC%), forced expiratory volume (FEV1%), and the number of acute exacerbations were compared before and after treatment. Nasal biopsies were taken before and after treatment, and mRNA expression of MDR and CFTR was determined by in situ hybridization. A significant dose-dependent increase of Cl− efflux from CFBE cells (but not from 16HBE cells) was observed after AZM treatment. A CFTR inhibitor significantly reduced AZM-stimulated Cl−  efflux from CFBE cells. A significant improvement in FEV1%, and fewer exacerbations were observed. AZM treatment did not affect mRNA expression of MDR and CFTR. The stimulation of Cl− efflux could be part of the explanation for the clinical improvement seen among the patients.

  • 4.
    Varelogianni, Georgia
    Örebro University, School of Health and Medical Sciences.
    Chloride transport and inflammation in cystic fibrosis airways2011Doctoral 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).

    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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  • 5.
    Varelogianni, Georgia
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. University Hospital, Örebro, Sweden.
    Hussain, Rashida
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. University Hospital, Örebro, Sweden.
    Strid, Hilja
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. University Hospital, Örebro, Sweden.
    Oliynyk, Igor
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. University Hospital, Örebro, Sweden.
    Roomans, Godfried M.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. University Hospital, Örebro, Sweden.
    Johannesson, Marie
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. University Hospital, Örebro, Sweden; Karolinska Institutet, Stockholm, Sweden.
    The effect of ambroxol on chloride transport, CFTR and ENaC in cysticfibrosis airway epithelial cells2013In: Cell Biology International, ISSN 1065-6995, E-ISSN 1095-8355, Vol. 37, no 11, p. 1149-1156Article in journal (Refereed)
    Abstract [en]

    Ambroxol, a mucokinetic anti-inflammatory drug, has been used for treatment of cystic fibrosis (CF). The respiratoryepitheliumis covered by the airway surface liquid (ASL), the thickness and composition of which is determined by Cl efflux viathe cystic fibrosis transmembrane conductance regulator (CFTR) and Naþ influx via the epithelial Naþ channel (ENaC). In cellsexpressing wt-CFTR, ambroxol increased the Cl- conductance, but not the bicarbonate conductance of the CFTR channels.Weinvestigated whether treatment with ambroxol enhances chloride transport and/or CFTR and ENaC expression in CF airwayepithelial cells (CFBE) cells. CFBE cells were treated with 100 mM ambroxol for 2, 4 or 8 h. mRNA expression for CFTR andENaC subunits was analysed by real-time polymerase chain reaction (RT-PCR); protein expression was measured by Westernblot. 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 theexpression of the mRNA of CFTR and a-ENaC, and of the CFTR protein. No significant difference was observed in b-ENaCafter exposure to ambroxol, whereasmRNA expression of g-ENaC was reduced. No significant effects of ambroxol on the ENaCsubunits were observed by Western blot. Ambroxol did not significantly affect the intracellular Ca2+ concentration.Upregulation of CFTR and enhanced Cl efflux after ambroxol treatment should promote transepithelial ion and watertransport, which may improve hydration of the mucus, and therefore be beneficial to CF-patients.

  • 6.
    Varelogianni, Georgia
    et al.
    Örebro University, School of Health and Medical Sciences.
    Oliynyk, Igor
    Örebro University, School of Health and Medical Sciences.
    Roomans, Godfried M.
    Örebro University, School of Health and Medical Sciences.
    Johannesson, Marie
    CF-center, Department of Women's and Children's Health, Academic Hospital, Uppsala, Sweden.
    The effect of N-acetylcysteine on chloride efflux from airway epithelial cells2010In: Cell Biology International, ISSN 1065-6995, E-ISSN 1095-8355, Vol. 34, no 3, p. 245-252Article in journal (Refereed)
    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.

  • 7.
    Varelogianni, Georgia
    et al.
    Örebro University, School of Health and Medical Sciences.
    Strid, Hilja
    Örebro University, School of Health and Medical Sciences.
    Oliynyk, Igor
    Örebro University, School of Health and Medical Sciences.
    Roomans, Godfried M.
    Örebro University, School of Health and Medical Sciences.
    Johannesson, Marie
    Örebro University, School of Health and Medical Sciences.
    The effect of ambroxol on chloride transport and mRNA expression of CFTR and ENaC in cystic fibrosis airway epithelial cellsManuscript (preprint) (Other academic)
  • 8.
    Varelogianni, Georgia
    et al.
    Örebro University, School of Health and Medical Sciences.
    Strid, Hilja
    Örebro University, School of Health and Medical Sciences.
    Särndahl, Eva
    Örebro University, School of Health and Medical Sciences.
    Björkqvist, Maria
    Örebro university hospital, Department of pediatrics.
    Roomans, Godfried M.
    Örebro University, School of Health and Medical Sciences.
    Decreased expression of Nod2-receptors and production of pro-inflammatory cytokines in cystic fibrosis airway epithelial cellsManuscript (preprint) (Other academic)
1 - 8 of 8
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