Abstract
Background: ER stress in type II alveolar epithelial cells (AECs) and lung macrophages has been linked with the development of IPF. The KCa3.1 has been proposed as a novel target for IPF that activates cell types involved in the disease. While KCa3.1 is expressed in AECs and macrophages, its association with ER stress during the disease process is unclear.
Aims: We utilised a novel sheep model of pulmonary fibrosis to demonstrate that Senicapoc, a selective inhibitor of KCa3.1 ion channel, will ameliorate ER stress in type II AECs and macrophages. We hypothesize that this process contributes to the drug’s overall anti-fibrotic effects.
Methods: Single lung segments of 30 sheep were bronchoscopically instilled with 2 doses of bleomycin, 2 weeks apart, to induce localised fibrosis. 30 sheep were assigned into 3 groups and given 2 daily doses (30 mg/kg) of either: Senicapoc; Pirfenidone; or methylcellulose (vehicle) for 5 weeks before culling. Lung tissue sections were immuno-stained with GRP78 BiP antibody to identify ER stressed cells. Positively stained cells were counted in 20 fields (40X).
Results: Both Senicapoc and Pirfenidone treatments significantly reduced the rate of ER stress in type II AECs (Senicapoc 0.26±0.06 vs 0.68±0.12 cells/field in vehicle, n=10 p=0.002; Pirfenidone 0.36±0.04 vs 0.68±0.12 cells/field in vehicle, p=0.01). However, only Senicapoc reduced the rate of ER stress in macrophages (Senicapoc 0.47±0.11 vs 1.46±0.42 cells/field in vehicle, p=0.017; Pirfenidone 0.86±0.11 vs 1.46±0.42 cells/field in vehicle, p=0.2).
Conclusion: Senicapoc alleviates ER stress in type II AECs and macrophages which contributes to the drugs antifibrotic effects.
Footnotes
Cite this article as: European Respiratory Journal 2019; 54: Suppl. 63, PA5385.
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 2019