dc.contributor.author | Roach, KM | en_US |
dc.contributor.author | Sutcliffe, A | en_US |
dc.contributor.author | Matthews, L | en_US |
dc.contributor.author | Elliott, G | en_US |
dc.contributor.author | Newby, C | en_US |
dc.contributor.author | Amrani, Y | en_US |
dc.contributor.author | Bradding, P | en_US |
dc.date.accessioned | 2019-01-30T12:48:44Z | |
dc.date.available | 2017-12-14 | en_US |
dc.date.issued | 2018-01-10 | en_US |
dc.identifier.uri | https://qmro.qmul.ac.uk/xmlui/handle/123456789/55012 | |
dc.description.abstract | Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited therapeutic options. KCa3.1 ion channels play a critical role in TGFβ1-dependent pro-fibrotic responses in human lung myofibroblasts. We aimed to develop a human lung parenchymal model of fibrogenesis and test the efficacy of the selective KCa3.1 blocker senicapoc. 2 mm3 pieces of human lung parenchyma were cultured for 7 days in DMEM ± TGFβ1 (10 ng/ml) and pro-fibrotic pathways examined by RT-PCR, immunohistochemistry and collagen secretion. Following 7 days of culture with TGFβ1, 41 IPF- and fibrosis-associated genes were significantly upregulated. Immunohistochemical staining demonstrated increased expression of ECM proteins and fibroblast-specific protein after TGFβ1-stimulation. Collagen secretion was significantly increased following TGFβ1-stimulation. These pro-fibrotic responses were attenuated by senicapoc, but not by dexamethasone. This 7 day ex vivo model of human lung fibrogenesis recapitulates pro-fibrotic events evident in IPF and is sensitive to KCa3.1 channel inhibition. By maintaining the complex cell-cell and cell-matrix interactions of human tissue, and removing cross-species heterogeneity, this model may better predict drug efficacy in clinical trials and accelerate drug development in IPF. KCa3.1 channels are a promising target for the treatment of IPF. | en_US |
dc.description.sponsorship | This work was supported by The Dunhill Medical Trust, project grant R270/1112, the MRC, project grant MR/K018213/1, and The British Lung Foundation, grant PPRG15-8. The work was also supported in part by the National Institute for Health Research Leicester Respiratory Biomedical Research Unit. | en_US |
dc.format.extent | 342 - ? | en_US |
dc.language | eng | en_US |
dc.language.iso | en | en_US |
dc.relation.ispartof | Sci Rep | en_US |
dc.rights | Creative Commons Attribution License | |
dc.rights | Attribution 3.0 United States | * |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/us/ | * |
dc.subject | Cell Survival | en_US |
dc.subject | Cells, Cultured | en_US |
dc.subject | Collagen | en_US |
dc.subject | Dexamethasone | en_US |
dc.subject | Energy Metabolism | en_US |
dc.subject | Fibroblasts | en_US |
dc.subject | Gene Expression Profiling | en_US |
dc.subject | Humans | en_US |
dc.subject | Idiopathic Pulmonary Fibrosis | en_US |
dc.subject | Immunohistochemistry | en_US |
dc.subject | Intermediate-Conductance Calcium-Activated Potassium Channels | en_US |
dc.subject | Models, Biological | en_US |
dc.subject | Tissue Culture Techniques | en_US |
dc.subject | Transcriptome | en_US |
dc.subject | Transforming Growth Factor beta1 | en_US |
dc.title | A model of human lung fibrogenesis for the assessment of anti-fibrotic strategies in idiopathic pulmonary fibrosis. | en_US |
dc.type | Article | |
dc.rights.holder | The Author(s) 2017 | |
dc.identifier.doi | 10.1038/s41598-017-18555-9 | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/29321510 | en_US |
pubs.issue | 1 | en_US |
pubs.notes | Not known | en_US |
pubs.publication-status | Published online | en_US |
pubs.volume | 8 | en_US |
dcterms.dateAccepted | 2017-12-14 | en_US |
rioxxterms.funder | Default funder | en_US |
rioxxterms.identifier.project | Default project | en_US |