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10.1186/s13069-015-0022-0

http://scihub22266oqcxt.onion/10.1186/s13069-015-0022-0
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suck abstract from ncbi


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pmid25829947      Fibrogenesis+Tissue+Repair 2015 ; 8 (ä): ä
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  • Human lung myofibroblast TGF?1-dependent Smad2/3 signalling is Ca2+-dependent and regulated by KCa3 1 K+ channels #MMPMID25829947
  • Roach KM; Feghali-Bostwick C; Wulff H; Amrani Y; Bradding P
  • Fibrogenesis Tissue Repair 2015[]; 8 (ä): ä PMID25829947show ga
  • 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 ?-SMA and Smad2/3 nuclear translocation in IPF-derived human lung myofibroblasts (HLMFs), and inhibits several transforming growth factor beta 1 (TGF?1)-dependent cell processes. We hypothesized that KCa3.1-dependent cell processes also regulate the TGF?1-dependent Smad2/3 signalling pathway in HLMFs. HLMFs obtained from non-fibrotic controls (NFC) and IPF lungs were grown in vitro and examined for ?SMA 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 TGF?1-dependent signalling. Expression of phosphorylated and total Smad2/3 following TGF?1 stimulation was determined by Western blot and Smad2/3 nuclear translocation by immunofluorescence. Results: KCa3.1 block attenuated TGF?1-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 (?SMA, collagen type I), inhibited KCa3.1 mRNA expression, and attenuated TGF?1-dependent ?SMA protein expression. Conclusions: KCa3.1 activity regulates TGF?1-dependent effects in NFC- and IPF-derived primary HLMFs through the regulation of the TGF?1/Smad signalling pathway, with promotion of downstream gene transcription and protein expression. KCa3.1 blockers may offer a novel approach to treating IPF. Electronic supplementary material: The online version of this article (doi:10.1186/s13069-015-0022-0) contains supplementary material, which is available to authorized users.
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