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The effect of S-nitrosoglutathione and L-cysteine on chloride efflux from cystic fibrosis airway epithelial cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
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2011 (English)In: Experimental and molecular pathology (Print), ISSN 0014-4800, E-ISSN 1096-0945, Vol. 90, no 1, 79-83 p.Article in journal (Refereed) Published
Abstract [en]

The endogenous bronchodilator, S-nitrosoglutathione (GSNO), has been proposed as a possible pharmacological remedy that reverses the Delta F508-CFTR (cystic fibrosis transmembrane conductance regulator) maturation defect and increases CFTR-mediated chloride efflux in cultured cystic fibrosis airway epithelial cells (CFBE41o(-)). It has also been reported that L-cysteine enhanced S-nitrosothiol uptake and increased the intracellular S-nitrosothiol levels, likely through transnitrosation chemistry. The present study investigated whether L-cysteine augmented the effect of GSNO on chloride efflux from CF airway epithelial cells. Treatment with 10 mu M GSNO combined with 20 mu M L-cysteine resulted in increased chloride efflux from CFBE41o(-) cells after 5 minutes exposure compared to the control efflux rate and to the efflux rate in the presence of L-cysteine alone as measured using the fluorescent dye N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide (MQAE). Chloride efflux rates from these cells after 4 h exposure to GSNO and L-cysteine were not different from control. Treatment with 10 mu M GSNO alone increased chloride efflux from CFBE41o(-) cells after 4 h but not at shorter incubation times. GSNO with or without L-cysteine did not alter epithelial tight junction integrity. In conclusion, a combination of GSNO with L-cysteine led to significant increase in chloride efflux in CFBE41o(-) cells but the effect was transient and not sustained beyond minutes.

Place, publisher, year, edition, pages
2011. Vol. 90, no 1, 79-83 p.
Keyword [en]
Cystic fibrosis, S-nitrosoglutathione, L-cysteine, Chloride efflux, Airway epithelial cells
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-148133DOI: 10.1016/j.yexmp.2010.10.005ISI: 000286349300013PubMedID: 20965165OAI: oai:DiVA.org:uu-148133DiVA: diva2:401456
Available from: 2011-03-02 Created: 2011-03-02 Last updated: 2013-09-20Bibliographically approved
In thesis
1. Functional Aspects of Epithelia in Cystic Fibrosis and Asthma
Open this publication in new window or tab >>Functional Aspects of Epithelia in Cystic Fibrosis and Asthma
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP activated chloride channel in the apical membrane of epithelial cells, is defective in patients with cystic fibrosis (CF). Research efforts are focused on chloride channel function in order to find a cure for the disease.

Genistein increased chloride transport in normal and delF508-CFTR cultured airway epithelial cells without cAMP stimulation. Prior pretreatment with phenylbutyrate did not affect the rate of the genistein-stimulated chloride efflux in these cells.

S-nitrosoglutathione is an endogenous bronchodilator, present in decreased amounts in the lungs of CF patients. We studied the effect of GSNO on chloride (Cl-) transport in primary nasal epithelial cells from CF patients homozygous for the delF508-CFTR mutation, as well as in two CF cell lines, using a fluorescent Cl- indicator and X-ray microanalysis. GSNO increased chloride efflux in the CF cell lines and in primary nasal epithelial cells from CF patients. This effect was partly mediated by CFTR. If the cells were exposed to GSNO in the presence of L-cysteine, Cl- transport was enhanced after 5 min, but not after 4 h. GSNO may be a candidate for pharmacological treatment of CF patients.

Chloride transport properties of cultured NCL-SG3 sweat gland cells were investigated. The CFTR protein was neither functional nor expressed in these cells. Ca2+-activated chloride conductance was confirmed and the putative Ca2+-activated chloride channel (CaCC) was further characterized in term of its pharmacological sensitivity.

Corticosteroids, the primary treatment for asthma, cause necrosis/apoptosis of airway epithelial cells. It was investigated whether a newer generation of drugs used in asthma, leukotriene receptor antagonists, had similar effects. Both montelukast and dexamethasone, but not beclomethasone or budesonide induced apoptosis/necrosis in superficial airway epithelial cells. Montelukast and corticosteroids also caused decreased expression of intercellular adhesion molecule -1 (ICAM-1) in epithelial but not endothelial cells.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 91 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 361
Cell biology, cystic fibrosis, CFTR, chloride transport, airway epithelium, sweat gland, asthma, corticosteroids, montelukast, Cellbiologi
urn:nbn:se:uu:diva-8905 (URN)978-91-554-7224-5 (ISBN)
Public defence
2008-06-05, B7:113a, BMC, Husargatan 3, Uppsala, 13:15
Available from: 2008-05-15 Created: 2008-05-15 Last updated: 2013-09-20Bibliographically approved

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