Abstract
Background: The K+ ion channel KCa3.1 is present on alveolar epithelial cells (AECs) and is known to activate other key cells involved in pulmonary fibrosis. While KCa3.1 has been proposed as a novel target for IPF, its regulatory function(s) in type II AECs in a disease setting are unclear.
Aims: Our hypothesis is that Senicapoc, a selective inhibitor of KCa3.1 ion channels, will retard type II AEC turnover which will contribute to the drug’s anti-fibrotic effects in a novel large animal model of pulmonary fibrosis.
Methods: Fibrosis was induced in single lung segments of 30 sheep via bronchoscopic infusion of bleomycin. These animals were assigned into 3 groups and given 2 daily doses (30 mg/kg) of either: Senicapoc; Pirfenidone; or methylcellulose (vehicle control) for 5 weeks. Treated lung segments were assessed for apoptosis via the Tunel method. Cell proliferation was measured immunohistologically by counting Ki67-positive cells. Positively stained type II AECs were counted in 20 fields (40X mag) and values were expressed as group mean ± SEM.
Results: Senicapoc treatment significantly reduced the rate of apoptosis in type II AECs (Senicapoc 0.43±0.06 versus 0.94±0.16 apoptotic cells/field in controls, n=10 p=0.003). Pirfenidone administration did not significantly reduce the apoptotic rate in type II AECs (Pirfenidone 0.65±0.07 versus 0.94±0.16 apoptotic cells/field in controls, n=10). Cell proliferation was reduced by 36±5% in fibrotic lung segments in sheep treated with Senicapoc compared with vehicle controls (n=10, p=0.001).
Conclusion: Retarded turnover of type II AECs contributed to the overall antifibrotic effects of the KCa3.1 ion channel inhibitor Senicapoc.
Footnotes
Cite this article as: European Respiratory Journal 2018 52: Suppl. 62, PA3715.
This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only).
- Copyright ©the authors 2018