Antifibrotics and PDE4B inhibition supress pulmonary fibroblast proliferation

<bold>Aim:</bold> Idiopathic pulmonary fibrosis (IPF) is characterised by excessive fibroblast proliferation. This study examined the effect of nintedanib, pirfenidone and a PDE4B inhibitor, alone and in combination on human pulmonary fibroblast (HPF) proliferation. <bold>Methods:</bold> HPFs from 3 donors were cultured and plated at sub-confluence. Cells were treated with nintedanib (10 and 1000nM), pirfenidone (10 and 300µg/mL) or A33 (a PDE4B inhibitor) (0.1-10µM), alone and in combination and incubated over 96 hours. Proliferation was assessed using the Alamar Blue assay (respiration) and automated live cell imaging (confluency). <bold>Results:</bold> Nintedanib and pirfenidone inhibited cell proliferation at the highest concentrations (1000nM and 300 µg/mL respectively) individually and additively when the drugs were combined (Figure 1). A33 caused a concentration dependent inhibition of proliferation of cells (one-way ANOVA, p= 0.002; IC50 7.621µM; Emax, 89%; n=5), which was significant at 1 and 10 µM. Neither nintendanib nor pirfenidone potentiated the inhibitory effects of A33 and at the highest concentrations reduced the anti-proliferative effects of A33 (n=5). <bold>Conclusion:</bold> Nintedanib and pirfenidone had an additive antiproliferative effect on HPFs. A33 suppressed fibroblast proliferation, in line with the proposed utility of PDE4B drug therapy in IPF. Further work is needed to characterise the pharmacological interactions between nintedanib, pirfenidone and A33. <fig><object-id>erj;64/suppl_68/PA3379/F1</object-id><object-id>F1</object-id><object-id>F1</object-id><graphic></graphic></fig>