Open AccessThe K+ Channel KCa3.1 as a Novel Target for Idiopathic Pulmonary Fibrosis
Author(s) -
Katy M. Roach,
S. Mark Duffy,
William R. Coward,
Carol FeghaliBostwick,
Heike Wulff,
Peter Bradding
Publication year - 2013
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0085244
Subject(s) - myofibroblast , idiopathic pulmonary fibrosis , pathology , fibrosis , western blot , medicine , pulmonary fibrosis , lung , chemistry , biology , biochemistry , gene
Background Idiopathic pulmonary fibrosis (IPF) is a common, progressive and invariably lethal interstitial lung disease with no effective therapy. We hypothesised that K Ca 3.1 K + channel-dependent cell processes contribute to IPF pathophysiology.Methods K Ca 3.1 expression in primary human lung myofibroblasts was examined using RT-PCR, western blot, immunofluorescence and patch-clamp electrophysiology. The role of K Ca 3.1 channels in myofibroblast proliferation, wound healing, collagen secretion and contraction was examined using two specific and distinct K Ca 3.1 blockers (TRAM-34 and ICA-17043 [Senicapoc]).Results Both healthy non fibrotic control and IPF-derived human lung myofibroblasts expressed K Ca 3.1 channel mRNA and protein. K Ca 3.1 ion currents were elicited more frequently and were larger in IPF-derived myofibroblasts compared to controls. K Ca 3.1 currents were increased in myofibroblasts by TGFβ1 and basic FGF. K Ca 3.1 was expressed strongly in IPF tissue. K Ca 3.1 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 Ca 2+ . Conclusions K Ca 3.1 activity promotes pro-fibrotic human lung myofibroblast function. Blocking K Ca 3.1 may offer a novel approach to treating IPF with the potential for rapid translation to the clinic.