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The effect of ambroxol on chloride transport, CFTR and ENaC in cysticfibrosis airway epithelial cells
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. University Hospital, Örebro, Sweden.
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. University Hospital, Örebro, Sweden. (Prof. Godfried M Roomans)ORCID iD: 0000-0003-4946-3228
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. University Hospital, Örebro, Sweden.
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. University Hospital, Örebro, Sweden.
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2013 (English)In: Cell Biology International, ISSN 1065-6995, E-ISSN 1095-8355, Vol. 37, no 11, p. 1149-1156Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Hoboken, USA: Wiley-Blackwell, 2013. Vol. 37, no 11, p. 1149-1156
Keywords [en]
Airway epithelium, ambroxol, cystic fibrosis, Cl− efflux, CFTR; ENaC
National Category
Medical and Health Sciences Cell Biology
Research subject
Biomedicine
Identifiers
URN: urn:nbn:se:oru:diva-32769DOI: 10.1002/cbin.10146ISI: 000325489500002PubMedID: 23765701Scopus ID: 2-s2.0-84885861654OAI: oai:DiVA.org:oru-32769DiVA, id: diva2:679027
Funder
Swedish Heart Lung FoundationSwedish Research Council
Note

Funding Agencies:

Swedish Science Research Council 

Available from: 2013-12-13 Created: 2013-12-13 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Cell responses in infected and cystic fibrosis respiratory epithelium
Open this publication in new window or tab >>Cell responses in infected and cystic fibrosis respiratory epithelium
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Respiratory Epithelium. Örebro Studies in Medicine 99. Cystic fibrosis (CF) is caused by a mutation in a cAMP-activated chloride (Cl-) channel (CFTR). Mortality and morbidity in CF is mainly due to the deregulated responses of the airway epithelial cells. The purpose of the thesis was to investigate the behaviour of the airway epithelial cells that are involved in maintaining the homeostasis in the airways.

Nasal brush biopsies obtained from anesthetized human nasal mucosa can be an easy source to establish primary epithelial cell lines (Paper I). We found that CF and non CF cellular models cannot fully show the relation between CFTR and the phenotypic differences between CF and healthy cells (Paper II). The possibility to correct the Cl- transport defect in CF by the use of stable NOdonors, and ambroxol was investigated. NO-donors stimulated Cl- efflux, and decreased ENaC mRNA expression in CFBE cells (Paper III), while ambroxol increased Cl- efflux from CFBE cells, and showed a positive effect on the biosynthesis of CFTR (Paper IV). This suggests that these substances may be a potentially interesting group of compounds for the treatment of CF. Increased levels of IL-6 and IL-8 upon infection in CF cells can increase the susceptibility of P. aeruginosa infected CF cells to apoptosis and/or internalization of these bacteria in CF cells and hence, may have important roles in the pathology of P. aeruginosa infection in CF airways. If internalization is beneficial for the host then glucocorticoids (GCs) are not beneficial for the treatment of CF patients. However, GCs may improve airway hydration. Whether the benefits of GC treatment outweigh the negative effects is questionable, and further clinical studies need to be carried out (Paper V). The neonatal isolates S. epidermidis 94B080 and S. aureus 90B083 can modulate CFTR and ENaC expression in airway epithelial cells, which may disturb the ion transport in the respiratory epithelium upon bacterial exposure. Airway epithelial cells also show excessive inflammatory responses to these bacteria, which means that these bacteria may induce pulmonary inflammation (Paper VI).

Place, publisher, year, edition, pages
Örebro: Örebro universitet, 2014. p. 85
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 99
Keywords
airway epithelial cells, cystic fibrosis, bacterial infection, CFTR, ENaC, chloride transport, intracellular calcium, P. aeruginosa internalization
National Category
Biomedical Laboratory Science/Technology
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-32191 (URN)978-91-7668-984-4 (ISBN)
Public defence
2014-01-17, Bohmansalen, B-huset, Universitetssjukhuset i Örebro, S Grev Rosengatan 18, 703 62 Örebro, 11:57 (Swedish)
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Available from: 2013-10-29 Created: 2013-10-29 Last updated: 2017-10-17Bibliographically approved

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Varelogianni, GeorgiaHussain, RashidaStrid, HiljaOliynyk, IgorRoomans, Godfried M.Johannesson, Marie

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