New approach to the treatment of bleomycin-induced lung fibrosis using pulmonary surfactant as pirfenidone carrier into the lung

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressively and ultimately fatal lung disease. Bleomycin-induced lung fibrosis model show decreased activity of pulmonary surfactant (PS) followed by thickening of the septal wall and collagen deposition. PS is a complex mixture of lipids and proteins that reduce surface tension at the alveolar interface avoiding alveolar collapse. Chronic abnormally high surface tension contributes to fibrosis development by introducing mechanical stress. Besides, transforming growth factor beta 1 (TGF-β1) is a cytokine related to fibroblast recruitment and fibrosis development. Therefore, TGF-β1 blocking-based therapies have been developed in the last years. One example is pirfenidone (PFD), approved in Europe for use in IPF treatment. Interestingly, PFD is highly hydrophobic being thus a potential candidate for solubilization in lipids, such as PS lipids. Therefore, we aim to develop a therapy based in the combination of PS and PFD, benefiting from preventing mechanical stress and blocking TGF-β1. Moreover, fast spread of PS in alveolar airspaces would help to locally deliver PFD, targeting alveolar epithelium. Preliminary data from the combination of PS and PFD shows better lung performance, with increased compliance and normalized elastance. Moreover, SP-C expression and inflammatory proteins show reversion to similar levels as in healthy controls. Combination therapy also shows decreased levels of TGF-β1 and PDGF compared to single therapies. In conclusion, combination therapy using PS as PFD carrier increases beneficial effects of both components.