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Title: Human lung myofibroblast TGFβ1-dependent Smad2/3 signalling is Ca(2+)-dependent and regulated by KCa3.1 K(+) channels.
Authors: Roach, Katy M.
Feghali-Bostwick, C.
Wulff, H.
Amrani, Yassine
Bradding, Peter
First Published: 26-Mar-2015
Publisher: BioMed Central
Citation: Fibrogenesis Tissue Repair, 2015, 8:5
Abstract: Background 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 KCa3.1
DOI Link: 10.1186/s13069-015-0022-0
ISSN: 1755-1536
eISSN: 1755-1536
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
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) (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.
Description: PMCID: PMC4379608 PMID: 25829947 [PubMed]
Appears in Collections:Published Articles, Dept. of Infection, Immunity and Inflammation

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