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Corticosteroids and Montelukast: Effects on Airway Epithelial and Human Umbilical Vein Endothelial Cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
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2010 (English)In: Lung, ISSN 0341-2040, E-ISSN 1432-1750, Vol. 188, no 3, 209-216 p.Article in journal (Refereed) Published
Abstract [en]

Our primary objective was to investigate the possible contribution of controller medications to asthmatic airway remodeling, by (1) comparing the apoptotic and necrotic effects of several corticosteroids and montelukast on cultured airway human bronchial surface epithelial (16HBE) and submucosal (Calu3) cells; (2) measuring epithelial shedding potential and desmosome length in response to a cytokine challenge, with or without co-administered corticosteroids; and (3) studying corticosteroids and montelukast effects on inter-cellular adhesion molecule (ICAM) expression in both 16HBE and human umbilical vein endothelial cells (HUVEC). For this purpose, apoptosis, necrosis, and ICAM expression were quantified by flow cytometry, with 16HBE cells sensitive to both the apoptotic and necrotic effects of dexamethasone and montelukast; Calu3 cells sensitive only to budesonide. Transmission electron microscopy revealed decreased desmosome length in the presence of cytokines (TNF-alpha and INF-gamma), with corticosteroids counteracting this reduction. Dexamethasone, beclomethasone, and montelukast decreased versus increased ICAM-1 expression in airway epithelial cells and HUVEC, respectively. For conclusions, bronchial surface epithelial and submucosal cells exhibit a different sensitivity profile toward dexamethasone, budesonide, and montelukast, with corticosteroids preventing cytokineinduced desmosomal damage in 16HBE cells. The studied drugs led to increased ICAM-1 expression in endothelium, potentially facilitating inflammatory cell migration into lung tissue.

Place, publisher, year, edition, pages
2010. Vol. 188, no 3, 209-216 p.
Keyword [en]
Corticosteroids, Leukotriene receptor antagonist, Montelukast, Airway epithelium, Apoptosis, Desmosomes, ICAM
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-136340DOI: 10.1007/s00408-010-9227-6ISI: 000276910400004OAI: oai:DiVA.org:uu-136340DiVA: diva2:376701
Available from: 2010-12-13 Created: 2010-12-11 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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 361
Keyword
Cell biology, cystic fibrosis, CFTR, chloride transport, airway epithelium, sweat gland, asthma, corticosteroids, montelukast, Cellbiologi
Identifiers
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
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Available from: 2008-05-15 Created: 2008-05-15 Last updated: 2013-09-20Bibliographically approved

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