Disulfiram activation of prostaglandin E2 synthesis: a novel antifibrotic mechanism in pulmonary fibrosis.

Abstract

Idiopathic pulmonary fibrosis (IPF) is characterized by the pathological replacement of alveolar structures with thickened, inelastic fibrous tissue, which significantly hinders gas exchange in the lungs. Disulfiram (DSF), a Food and Drug Administration-approved drug for alcohol dependence, has shown potential in various diseases. This study investigates the effects of DSF on IPF and its mechanisms, focusing on the cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway. Utilizing primary diseased human lung fibroblast-IPF cells and A549 cells induced with transforming growth factor-beta 1 to model epithelial-mesenchymal transition (EMT), we employed a battery of in vitro assays to assess cellular viability, migratory capacity, and the expression of fibrosis-related genes and proteins. To further substantiate our in vitro findings, a bleomycin-induced mouse model of IPF was treated with DSF, and subjected to a comprehensive evaluation of pulmonary function, histological examination, hydroxyproline assay, and western blot analysis to quantify the extent of fibrosis. DSF reduced cell viability and migration in fibrotic cell models. It increased COX-2 and PGE2 levels, regulated EMT, and extracellular matrix collagen deposition. In vivo, DSF improved pulmonary function and reduced EMT and extracellular matrix accumulation in mice. The COX-2/PGE2 axis was identified as a critical mediator of DSF's effects. DSF exhibits antifibrotic properties in IPF by modulating the COX-2/PGE2 signaling pathway. This study provides a novel therapeutic strategy for IPF and highlights the potential of repurposing DSF for clinical use in this context. SIGNIFICANCE STATEMENT: Disulfiram shows promise in treating idiopathic pulmonary fibrosis by targeting the cyclooxygenase-2/prostaglandin E2 pathway, offering a new therapeutic strategy and highlighting its potential for repurposing in this context.