Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with limited therapeutic options and poor prognosis. IPF has been associated with aberrant vascular remodelling, however the role of vascular remodelling in pulmonary fibrosis is poorly understood. Here, we used a novel segmental challenge model of bleomycin-induced pulmonary fibrosis in sheep to evaluate the remodelling of the pulmonary vasculature, and to investigate the changes to this remodelling after the administration of the KCa3.1 channel inhibitor, senicapoc, compared to the FDA-approved drug pirfenidone. We demonstrate that in vehicle-treated sheep, bleomycin-infused lung segments had significantly higher blood vessel density when compared to saline-infused control segments in the same sheep. These microvascular density changes were significantly attenuated by senicapoc treatment. The increases in vascular endothelial growth factor (VEGF) expression and endothelial cell proliferation in bleomycin-infused lung segments were significantly reduced in sheep treated with the senicapoc, when compared to vehicle-treated controls. These parameters were not significantly suppressed with pirfenidone treatment. Senicapoc treatment attenuated vascular remodelling through inhibition of capillary endothelial cell proliferation and VEGF expression. These findings suggest a potential new mode of action for the novel drug senicapoc which may contribute to its efficacy in combatting pulmonary fibrosis.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with limited therapeutic options and poor prognosis
The pathogenesis of IPF is poorly understood, though current paradigms focus on alveolar epithelial cell injury as a key initiating event followed by dysregulated wound healing process resulting in fibrosis and distortion of the lung’s architecture
This study evaluates the presence of vascular remodelling during the development of bleomycin-induced pulmonary fibrosis and investigates the effects senicapoc on vascular remodelling when compared to the FDA-approved drug pirfenidone
Summary
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with limited therapeutic options and poor prognosis. The pathogenesis of IPF is poorly understood, though current paradigms focus on alveolar epithelial cell injury as a key initiating event followed by dysregulated wound healing process resulting in fibrosis and distortion of the lung’s architecture During this process, injuries to the lung damage the normal lung parenchyma and affects the pulmonary vasculature leading to an aberrant vascular remodelling[1]. We have recently developed a physiologically and pharmacologically relevant large animal model for pulmonary fibrosis which allows for the exploration of the disease mechanisms, as well as for the investigation of new treatments for this disease[14] In this model, fibrotic remodelling and correspondingly poor lung function has been shown to persist for at least seven weeks after bleomycin injury[15,16] making it a useful preclinical model to investigate novel anti-fibrotic therapeutic agents
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