title: Inhibition of the KCa3.1 Channel Alleviates Established Pulmonary Fibrosis in a Large Animal Model.
abstract: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease of increasing prevalence marked by poor prognosis and limited treatment options. Ca2+-activated KCa3.1 potassium channels have been shown to play a key role in the aberrant activation and responses to injury in both epithelial cells and fibroblasts, both considered key drivers in the fibrotic process of IPF. Pharmacological inhibition of IPF-derived fibroblasts is able to somewhat prevent TGF-β- and basic fibroblast growth factor-dependent profibrotic responses. In the current study, we investigated whether blockade of the KCa3.1 ion channel in vivo with a selective inhibitor, Senicapoc, was able to attenuate both histological and physiological outcomes of early fibrosis in our large animal (sheep) model for pulmonary fibrosis. We also determined whether treatment was targeting the profibrotic activity of sheep lung fibroblasts. Senicapoc was administered in established fibrosis, at 2 weeks after bleomycin instillation, and drug efficacy was assessed 4 weeks after treatment. Treatment with Senicapoc improved pre-established bleomycin-induced changes compared with vehicle control, leading to improved lung compliance, reduced extracellular matrix and collagen deposition, and a reduction in both α-smooth muscle actin expression and proliferating cells, both in vivo and in vitro. These studies show that inhibiting the KCa3.1 ion channel is able to attenuate the early fibrogenic phase of bleomycin-dependent fibrosis and inhibits profibrotic behavior of primary sheep lung fibroblasts. This supports the previous research conducted in human IPF-derived fibroblasts and suggests that inhibiting KCa3.1 signaling may provide a novel therapeutic approach for IPF.
authors.affiliation: 1 Faculty of Veterinary and Agricultural Science, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Louise
authors.initials: L
authors.lastname: Organ
authors.affiliation: 2 School of Veterinary Medicine, University of Surrey, Guildford, United Kingdom.
authors.forename: Barbara
authors.initials: B
authors.lastname: Bacci
authors.affiliation: 3 Department of Electrical and Electronic Engineering, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Koumoundouros
authors.affiliation: 1 Faculty of Veterinary and Agricultural Science, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Wayne G
authors.initials: WG
authors.lastname: Kimpton
authors.affiliation: 4 Cardiovascular Disease Program, Biomedical Discovery Institute and Department of Pharmacology, Monash University, Clayton, Victoria, Australia.
authors.forename: Chrishan S
authors.initials: CS
authors.lastname: Samuel
authors.affiliation: 5 Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors.forename: Cameron J
authors.initials: CJ
authors.lastname: Nowell
authors.affiliation: 6 Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester, Leicester, United Kingdom; and.
authors.forename: Peter
authors.initials: P
authors.lastname: Bradding
authors.affiliation: 6 Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester, Leicester, United Kingdom; and.
authors.forename: Katy M
authors.initials: KM
authors.lastname: Roach
authors.affiliation: 7 Department of Allergy, Immunology and Respiratory Medicine, Alfred Hospital Melbourne, Victoria, Australia.
authors.forename: Glen
authors.initials: G
authors.lastname: Westall
authors.affiliation: 7 Department of Allergy, Immunology and Respiratory Medicine, Alfred Hospital Melbourne, Victoria, Australia.
authors.forename: Jade
authors.initials: J
authors.lastname: Jaffar
authors.affiliation: 1 Faculty of Veterinary and Agricultural Science, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Ken J
authors.initials: KJ
authors.lastname: Snibson
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000818:Animals; D001761:Bleomycin; D003187:Compliance; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005455:Fluorescent Antibody Technique; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D011658:Pulmonary Fibrosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D012129:Respiratory Function Tests; D012756:Sheep; D014320:Triphenylmethyl Compounds / Q000494:pharmacology
chemical_list: D000081:Acetamides; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D014320:Triphenylmethyl Compounds; D001761:Bleomycin; C472774:senicapoc
keywords: bleomycin; fibrosis; novel therapeutics; potassium calcium ion channel