Journal Article

Inhibition of the KCa3.1 Channel Alleviates Established Pulmonary Fibrosis in a Large Animal Model

Snibson, Ken J., Koumoundouros, Emmanuel, Roach, Katy M., Organ, Louise, Bacci, Barbara, Jaffar, Jade, Kimpton, Wayne G., Samuel, Chrishan S., Westall, Glen, Bradding, Peter, Nowell, Cameron J.

2017

Overview

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.

• Publisher: Oxford University Press
• Subject: Actin / Animal models / Bleomycin / Epithelial cells / Extracellular matrix / Fibroblast growth factor 2 / Fibroblasts / Fibrosis / Lung diseases / Potassium channels (calcium-gated) / Pulmonary fibrosis / Sheep / Smooth muscle / Transforming growth factor-b