Differential effects of the histone deacetylase (HDAC) inhibitor, Romidepsin (FK228), on IPF fibroblasts and alveolar epithelial cells.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a poor prognosis (~3-yr median survival from diagnosis). Numerous ‘single pathway’ agents have failed to show efficacy in IPF clinical trials [ 1 ] . By targeting multiple genes and pathways, HDAC inhibitors offer a novel therapeutic strategy that could be used alone or in combination with existing agents (Pirfenidone and Nintedanib). This work investigated the specific effects of the HDAC inhibitor, Romidepsin on primary fibroblasts and alveolar type 2 (ATII) epithelial cells. Our results showed that Romidepsin caused a strong inhibition of IPF fibroblast proliferation by inducing cell cycle arrest. Moreover, Romidepsin inhibited fibroblast contraction and migration, both key mechanisms in the scarring process. Comparison of the effect of Romidepsin treatment on ATII cells and IPF fibroblasts showed that the fibroblasts were significantly more sensitive to growth inhibition compared to ATII cells. Furthermore, Romidepsin treatment did not affect the unique ability of ATII cells to produce surfactants. Using proteomic analysis, we were able to identify 53 secreted proteins that were significantly modulated in IPF fibroblasts treated with Romidepsin, offering potential for future biomarker studies. In conclusion, Romidepsin has potent anti-fibrotic effects on IPF fibroblasts by inducing cell cycle arrest and inhibition of cell migration and contraction. Significantly it has no harmful effects on ATII cells that could help to rebuild the alveolar epithelium limiting the progression of fibrosis. Identification of biomarkers will facilitate analysis of the efficacy of Romidepsin therapy in a future clinical trial and help to characterize better this devastating disease.