The K+ channel KCa3.1 as a novel target for idiopathic pulmonary fibrosis

Katy Morgan Roach, Stephen Mark Duffy, William Coward, Carol Feghali-Bostwick, Heike Wulff, Peter Bradding

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a common, progressive and invariably lethal interstitial lung disease with no effective therapy. We hypothesised that KCa3.1 K+ channel-dependent cell processes contribute to IPF pathophysiology. Methods: KCa3.1 expression in primary human lung myofibroblasts was examined using RT-PCR, western blot, immunofluorescence and patch-clamp electrophysiology. The role of KCa3.1 channels in myofibroblast proliferation, wound healing, collagen secretion and contraction was examined using two specific and distinct KCa3.1 blockers (TRAM-34 and ICA-17043 [Senicapoc]). Results: Both healthy non fibrotic control and IPF-derived human lung myofibroblasts expressed KCa3.1 channel mRNA and protein. KCa3.1 ion currents were elicited more frequently and were larger in IPF-derived myofibroblasts compared to controls. KCa3.1 currents were increased in myofibroblasts by TGFβ1 and basic FGF. KCa3.1 was expressed strongly in IPF tissue. KCa3.1 pharmacological blockade attenuated human myofibroblast proliferation, wound healing, collagen secretion and contractility in vitro, and this was associated with inhibition of TGFβ1-dependent increases in intracellular free Ca2+. Conclusions: KCa3.1 activity promotes pro-fibrotic human lung myofibroblast function. Blocking KCa3.1 may offer a novel approach to treating IPF with the potential for rapid translation to the clinic.

Original languageEnglish (US)
Article numbere85244
JournalPLoS One
Volume8
Issue number12
DOIs
StatePublished - Dec 31 2013

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    Roach, K. M., Duffy, S. M., Coward, W., Feghali-Bostwick, C., Wulff, H., & Bradding, P. (2013). The K+ channel KCa3.1 as a novel target for idiopathic pulmonary fibrosis. PLoS One, 8(12), [e85244]. https://doi.org/10.1371/journal.pone.0085244