Abstract
Drug development for idiopathic pulmonary fibrosis (IPF) has been limited due to poor translational efficacy of mouse-based in-vivo models. The KCa3.1 ion channel is thought to be implicated in IPF pathophysiology. This study uses both in vivo and in vitro based approaches to investigate the potential of using a selective inhibitor of KCa3.1 as a novel treatment for IPF.
For animal-based studies, two separate lung segments in twenty sheep received two fortnightly instillations of either the fibrotic agent bleomycin (BLM, 3U), or saline (control). Two weeks after the final BLM dose, sheep were randomly assigned to treatment groups (10 per group) and received twice daily oral administrations of either 30 mg/kg Senicapoc (ICA-17073), a selective inhibitor of KCa3.1, or vehicle alone (control 0.5% methylcellulose) for 7 weeks. Sheep treated with Senicapoc have reduced pathology scores in BLM-treated segments when compared to control sheep (4.6 ± 1.6 vs. 12.82 ± 1.7, n=10, p=0.001 [figure 1]. BLM-induced lung function decline was also prevented in Senicapoc treated sheep.
We then investigated the effects of Senicapoc using lung fibroblasts derived from sheep (n=4) and the Human fetal lung (HFL-1) fibroblast cell line. Cells were treated with Senicapoc in the presence/absence of fetal bovine serum (FBS). Treatment 100mM Senicapoc inhibited cell proliferation of both ovine and human fibroblasts in the presence of 10% FBS.
This study demonstrates that Senicapoc impedes fibrotic responses in the lungs and one of its modes of action is via the inhibition of fibroblast proliferation. This suggests that KCa3.1 channel blockade may be a useful tool against pulmonary fibrosis.
- Copyright ©the authors 2016
