Disulfiram Exerts anti-pulmonary Fibrosis Effect by Activating PGE2 Synthesis

Abstract

Idiopathic pulmonary fibrosis (IPF) is marked with the replacement of normal alveolar tissue by thicker and harder fibrous material, damaged exchange ability. Currently, nintedanib and pirfenidone, are the only FDA-approved drugs with limited efficacy for IPF, which indicated an urgent need to explore new therapies. Disulfiram (DSF), an acetaldehyde dehydrogenase inhibitor, used as anti-alcohol treatment. Despite reported with anti-hepatic fibrosis effect of DSF, the underlying mechanism remains unclear. In our study, DSF exhibited regulative impact on abnormal proliferation, EMT and ECM production in cell models of IPF including primary DHLF-IPF cells and TGF-{beta}1-stimulated A549 cells. The absence of COX-2 was restored by DSF treatment, together with elevated prostaglandin biosynthesis both in vitro and in vivo models of IPF. Furthermore, the anti-fibrotic effect of DSF was impeded with COX-2 knockdown or pharmacological inhibition in TGF-{beta}1-stimulated A549 cells, however, exogenous PGE2 reclaimed with anti-EMT function. In established animal model of IPF, DSF ameliorated declined lung function and histopathological changes, and restrained the lung hydroxyproline content. Together, these findings suggest that the anti-fibrotic effect of DSF was achieved through re-activation of COX-2 mediated PGE2 biosynthesis. The above results suggest that DSF can be applied therapeutically in fibrotic conditions.