PMID- 25829947
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20150401
LR  - 20220129
IS  - 1755-1536 (Print)
IS  - 1755-1536 (Electronic)
IS  - 1755-1536 (Linking)
VI  - 8
DP  - 2015
TI  - Human lung myofibroblast TGFbeta1-dependent Smad2/3 signalling is Ca(2+)-dependent 
      and regulated by KCa3.1 K(+) channels.
PG  - 5
LID - 10.1186/s13069-015-0022-0 [doi]
LID - 5
AB  - 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 alpha-SMA and Smad2/3 nuclear translocation in 
      IPF-derived human lung myofibroblasts (HLMFs), and inhibits several transforming 
      growth factor beta 1 (TGFbeta1)-dependent cell processes. We hypothesized that 
      KCa3.1-dependent cell processes also regulate the TGFbeta1-dependent Smad2/3 
      signalling pathway in HLMFs. HLMFs obtained from non-fibrotic controls (NFC) and 
      IPF lungs were grown in vitro and examined for alphaSMA 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 TGFbeta1-dependent signalling. Expression of phosphorylated and 
      total Smad2/3 following TGFbeta1 stimulation was determined by Western blot and 
      Smad2/3 nuclear translocation by immunofluorescence. RESULTS: KCa3.1 block 
      attenuated TGFbeta1-dependent Smad2/3 phosphorylation and nuclear translocation, and 
      this was mimicked by lowering the extracellular Ca(2+) concentration. KCa3.1 
      block also inhibited Smad2/3-dependent gene transcription (alphaSMA, collagen type 
      I), inhibited KCa3.1 mRNA expression, and attenuated TGFbeta1-dependent alphaSMA protein 
      expression. CONCLUSIONS: KCa3.1 activity regulates TGFbeta1-dependent effects in 
      NFC- and IPF-derived primary HLMFs through the regulation of the TGFbeta1/Smad 
      signalling pathway, with promotion of downstream gene transcription and protein 
      expression. KCa3.1 blockers may offer a novel approach to treating IPF.
FAU - Roach, Katy M
AU  - Roach KM
AD  - Department of Infection, Immunity and Inflammation, Institute for Lung Health, 
      University of Leicester, Glenfield Hospital, Groby Road, Leicester, LE3 9QP UK.
FAU - Feghali-Bostwick, Carol
AU  - Feghali-Bostwick C
AD  - Department of Medicine, Division of Rheumatology and Immunology, University of 
      South Carolina, Columbia, SC 29208 USA.
FAU - Wulff, Heike
AU  - Wulff H
AD  - Department of Pharmacology, University of California, 451 Health Sciences Drive, 
      Davis, CA 95616 USA.
FAU - Amrani, Yassine
AU  - Amrani Y
AD  - Department of Infection, Immunity and Inflammation, Institute for Lung Health, 
      University of Leicester, Glenfield Hospital, Groby Road, Leicester, LE3 9QP UK.
FAU - Bradding, Peter
AU  - Bradding P
AD  - Department of Infection, Immunity and Inflammation, Institute for Lung Health, 
      University of Leicester, Glenfield Hospital, Groby Road, Leicester, LE3 9QP UK.
LA  - eng
GR  - K24 AR060297/AR/NIAMS NIH HHS/United States
GR  - R01 GM076063/GM/NIGMS NIH HHS/United States
GR  - R270/1112/DMT_/The Dunhill Medical Trust/United Kingdom
PT  - Journal Article
DEP - 20150326
PL  - England
TA  - Fibrogenesis Tissue Repair
JT  - Fibrogenesis & tissue repair
JID - 101464642
PMC - PMC4379608
OTO - NOTNLM
OT  - Human lung myofibroblast
OT  - Idiopathic pulmonary fibrosis
OT  - Potassium channel KCa3.1
EDAT- 2015/04/02 06:00
MHDA- 2015/04/02 06:01
PMCR- 2015/03/26
CRDT- 2015/04/02 06:00
PHST- 2014/12/10 00:00 [received]
PHST- 2015/03/05 00:00 [accepted]
PHST- 2015/04/02 06:00 [entrez]
PHST- 2015/04/02 06:00 [pubmed]
PHST- 2015/04/02 06:01 [medline]
PHST- 2015/03/26 00:00 [pmc-release]
AID - 22 [pii]
AID - 10.1186/s13069-015-0022-0 [doi]
PST - epublish
SO  - Fibrogenesis Tissue Repair. 2015 Mar 26;8:5. doi: 10.1186/s13069-015-0022-0. 
      eCollection 2015.