title: The K+ channel KCa3.1 as a novel target for idiopathic pulmonary fibrosis.
abstract: 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.
authors.forename: Katy M
authors.initials: KM
authors.lastname: Roach
authors.affiliation: Institute for Lung Health, Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom.
authors.forename: Katy Morgan
authors.initials: KM
authors.lastname: Roach
authors.affiliation: Institute for Lung Health, Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom.
authors.forename: Stephen Mark
authors.initials: SM
authors.lastname: Duffy
authors.affiliation: Division of Respiratory Medicine, Centre for Respiratory Research and Nottingham Respiratory Biomedical Research Unit, University of Nottingham, Nottingham, United Kingdom.
authors.forename: William
authors.initials: W
authors.lastname: Coward
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Carol
authors.initials: C
authors.lastname: Feghali-Bostwick
authors.affiliation: Department of Pharmacology, University of California Davis, Davis, California, United States of America.
authors.forename: Heike
authors.initials: H
authors.lastname: Wulff
authors.affiliation: Institute for Lung Health, Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Bradding
mesh_terms: D000704:Analysis of Variance; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D005455:Fluorescent Antibody Technique; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism / Q000503:physiopathology*; D007150:Immunohistochemistry; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058628:Myofibroblasts / Q000378:metabolism* / Q000502:physiology; D018408:Patch-Clamp Techniques; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology
chemical_list: D017931:DNA Primers; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; D053773:Transforming Growth Factor beta1; D003094:Collagen; D002118:Calcium