Oral Presentation International Veterinary Immunology Symposium 2016

The anti-inflammatory and anti-fibrotic effects Kca3.1 ion channel inhibition in sheep models of asthma and pulmonary fibrosis (#27)

Louise Organ 1 , Joanne Van der Velden 1 , Barbara Bacci 1 , Shane Ratnatilake 1 , Chrishan Samuel 2 , Donna Barker 1 , Garry Barcham 1 , Emmanuel Koumoudouros 1 , Wayne Kimpton 1 , Ken Snibson 1
  1. The University of Melbourne, Parkville, VICTORIA, Australia
  2. Monash University, Clayton, Victoria, Australia


The calcium-activated potassium ion channel KCa3.1 plays important roles in regulating cellular activities in the lungs that are integral to both inflammatory and fibrotic responses. Sheep provide useful in vivo systems to test novel therapeutics for human diseases, due to similarities in immunological and physiological responses between sheep and humans. Our laboratory investigated the efficacy of the KCa3.1 specific inhibitor Senicapoc (ICA-1704) on both inflammatory and fibrotic processes in sheep models of asthma and pulmonary fibrosis.

Methods For both the asthma and fibrosis models, two groups of 10 sheep received twice-daily oral doses of either 30mg/kg Senicapoc in methylcellulose or methylcellulose alone. Asthmatic sheep received fortnightly aerosol challenges with house dust mite (HDM), along with daily Senicapoc or methylcellulose treatments, for 14 weeks. In the fibrosis model, Senicapoc or vehicle control treatments commenced 2 weeks following bleomcyin instillation to induce fibrosis into one caudal lobe, with the opposite caudal lobe acting as a saline control. These treatments continued for 5 weeks.

Results In the asthma model, KCa3.1 blockade induced a significant reduction in both allergen-induced eosinophil recruitment (0.4±0.1 vs 1.6±0.5 [×10^5cells/mL], P<0.05) and mast cell infiltration (90±10, 38±11, 62±13, respectively P<0.05). In the fibrosis model, bleomycin-induced macrophage polarisation to M2 was reduced in the Senicapoc-treated sheep. In both models, KCa3.1 blockade reduced lung fibrosis and improved lung function compared to vehicle controls in the respective experimental settings.

Conclusions Senicapoc administration was able to decrease inflammatory responses involved in both sheep models of asthma and pulmonary fibrosis. These responses were associated with significant reductions in pathological remodelling of lung tissues, and resulted in improved lung function. Overall, the results highlight the usefulness of large animal models for studying respiratory diseases, especially where the inflammatory responses are associated with lung tissue structures that are relevant and comparable to the human lung