Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/31977
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dc.contributor.authorRoach, Katy M.-
dc.contributor.authorFeghali-Bostwick, C.-
dc.contributor.authorWulff, H.-
dc.contributor.authorAmrani, Yassine-
dc.contributor.authorBradding, Peter-
dc.date.accessioned2015-04-14T13:44:03Z-
dc.date.available2015-04-14T13:44:03Z-
dc.date.issued2015-03-26-
dc.identifier.citationFibrogenesis Tissue Repair, 2015, 8:5en
dc.identifier.issn1755-1536-
dc.identifier.urihttp://www.fibrogenesis.com/content/8/1/5en
dc.identifier.urihttp://hdl.handle.net/2381/31977-
dc.descriptionPMCID: PMC4379608 PMID: 25829947 [PubMed]en
dc.description.abstractBackground Idiopathic pulmonary fibrosis (IPF) is a common and invariably lethal interstitial lung disease with poorly effective therapy. Blockade of the K+ channel KCa3.1 reduces constitutive α-SMA and Smad2/3 nuclear translocation in IPF-derived human lung myofibroblasts (HLMFs), and inhibits several transforming growth factor beta 1 (TGFβ1)-dependent cell processes. We hypothesized that KCa3.1-dependent cell processes also regulate the TGFβ1-dependent Smad2/3 signalling pathway in HLMFs. HLMFs obtained from non-fibrotic controls (NFC) and IPF lungs were grown in vitro and examined for αSMA expression by immunofluorescence, RT-PCR, and flow cytometry. Two specific and distinct KCa3.1 blockers (TRAM-34 200 nM and ICA-17043 [Senicapoc] 100 nM) were used to determine their effects on TGFβ1-dependent signalling. Expression of phosphorylated and total Smad2/3 following TGFβ1 stimulation was determined by Western blot and Smad2/3 nuclear translocation by immunofluorescence. Results KCa3.1 block attenuated TGFβ1-dependent Smad2/3 phosphorylation and nuclear translocation, and this was mimicked by lowering the extracellular Ca2+ concentration. KCa3.1 block also inhibited Smad2/3-dependent gene transcription (αSMA, collagen type I), inhibited KCa3.1 mRNA expression, and attenuated TGFβ1-dependent αSMA protein expression. Conclusions KCa3.1 activity regulates TGFβ1-dependent effects in NFC- and IPF-derived primary HLMFs through the regulation of the TGFβ1/Smad signalling pathway, with promotion of downstream gene transcription and protein expression. KCa3.1 blockers may offer a novel approach to treating IPF. Keywords: Human lung myofibroblast; Idiopathic pulmonary fibrosis; Potassium channel KCa3.1en
dc.description.sponsorshipThis work was supported by The Dunhill Medical Trust, project grant R270/1112. The work was also supported in part by the National Institute for Health Research Leicester Respiratory Biomedical Research Unit. HW was supported by RO1 GM076063 from the National Institute of Health.en
dc.language.isoenen
dc.publisherBioMed Centralen
dc.relation.urihttp://www.ncbi.nlm.nih.gov/pubmed/25829947-
dc.rights© 2015 Roach et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0) (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.en
dc.subjectHuman lung myofibroblasten
dc.subjectIdiopathic pulmonary fibrosisen
dc.subjectPotassium channel KCa3.1en
dc.titleHuman lung myofibroblast TGFβ1-dependent Smad2/3 signalling is Ca(2+)-dependent and regulated by KCa3.1 K(+) channels.en
dc.typeJournal Articleen
dc.identifier.doi10.1186/s13069-015-0022-0-
dc.identifier.eissn1755-1536-
dc.description.statusPeer-revieweden
dc.description.versionPublisher Versionen
dc.type.subtypeJournal Article-
pubs.organisational-group/Organisationen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGYen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicineen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Infection, Immunity and Inflammationen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/Themesen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/Themes/Molecular & Cellular Bioscienceen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/Themes/Respiratory Scienceen
Appears in Collections:Published Articles, Dept. of Infection, Immunity and Inflammation

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