Differential effects of pirfenidone and nintedanib on mouse alveolar epithelial organoids

Manon Woest, Vicky Verschut, Reinoud Gosens, Loes Kistemaker

ERS International Congress 2020

Abstract

Rationale: Idiopathic pulmonary fibrosis is characterised by dysfunctional epithelial-mesenchymal communication and insufficient epithelial repair. Nintedanib and pirfenidone are the only approved pharmacological interventions for IPF that are known to affect the course of the disease. The mechanisms involved are not completely understood. Here, we aimed to investigate their effects on fibroblast-epithelial communication during alveolar organoid formation.
Methods: We co-cultured mouse lung fibroblasts (CCL206) with adult mouse CD31-/CD45-/EpCAM+ epithelial cells in organoids in the absence and presence of nintendanib (0.01-1 μM) or pirfenidone (0.1-2.5 mM) to investigate their capacity to support epithelial organoid formation in vitro. 
Results: Nintedanib concentration-dependently promoted, whereas pirfenidone concentration-dependently inhibited organoid formation. The effects were most outspoken at the 1 μM nintendanib concentration and at the 2.5 mM pirfenidone concentration. Nintedanib did not affect organoid size, whereas pirfenodine reduced organoid size at the highest concentration (2.5 mM). Both nintedanib and pirfenidone enhanced the presence of surfactant protein C (SFTPC) positive organoids in a concentration dependent fashion, at the expense of the number of Acetylated-tubulin (ACT) positive airway organoids.   
Conclusion: Pirfenidone and nintendanib have differential effects on alveolar organoid formation. Both treatments enhance the presence of alveolar type II cells in organoid culture, but only nintedanib enhanced the number of organoids in culture.