Abstract
Aims: To (i) investigate the effects of Romidepsin in vitro using fibroblasts and alveolar cells (ATII); (ii) in vivo in Bleomycin treated mice; and (iii) to identify biomarkers in order to monitor response to therapy in a future clinical trial.
Background: Idiopathic pulmonary fibrosis (IPF) is a complex chronic fibroproliferative disease of unknown aetiology and with limited therapeutic options.Numerous 'single pathway' agents have failed to show efficacy in IPF clinical trial. By targeting multiple genes and pathways, HDAC inhibitors offer novel therapeutic strategies that could be used alone or in combination with existing agents (Pirfenidone and Nintedanib).
Methods: Fibroblast and ATII cell proliferation were determined by cell counting and MTS assay. Myofibroblast differentiation was analysed by western blotting (WB) for α-SMA and Lysyl Oxidase (LOX). The antifibrotic effects of Romidepsin on bleomycin treated mice were assessed by RTqPCR, histology and WB. Broncho-alveolar-lavage (BAL) fluid from IPF patients was analysed by WB.
Results: Romidepsin caused a strong inhibition of IPF fibroblast proliferation, myofibroblast differentiation and secretion of LOX. Comparison of the effect of Romidepsin on ATII cells and IPF fibroblasts showed that the ATII cells were significantly less sensitive. Romidepsin reduced bleomycin-induced lung fibrosis in mice and suppressed the expression of LOX. We detected elevated levels of LOX in the BALF of IPF patients.
Conclusions: Romidepsin shows strong anti-fibrotic effects without harmful consequences on ATII cells. It is therefore a potential novel anti-fibrotic therapy and LOX may be a potential biomarker of response.
- Copyright ©the authors 2016
