Abstract

Purpose Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown cause, characterized by irreversible lung fibrosis, declining respiratory function, and high mortality. Phosphodiesterase 4 (PDE4) regulates physiological responses in immune and parenchymal cells by hydrolyzing cyclic adenosine monophosphate (cAMP), and its inhibition is regarded as an effective therapeutic strategy for pulmonary diseases. The PDE4 inhibitor DC591017 has demonstrated potent anti-inflammatory activity. However, its therapeutic efficacy and the underlying mechanisms in IPF remain unclear. Methods The bleomycin (BLM)-induced mouse model of pulmonary fibrosis was employed to evaluate the in vivo pharmacodynamics of orally administered DC591017. Furthermore, in vitro studies elucidated the cellular mechanisms of DC591017, highlighting its role in modulating lung fibroblasts, epithelial cells, and macrophages. Lung-on-a-chip models to further evaluate the regulatory effect of DC591017 on the macrophages-fibroblasts-epithelial cells microenvironment. Results Oral administration of DC591017 (10 mg/kg) significantly mitigated weight loss, improved histopathological lung damage, and reduced collagen deposition, accompanied by lung function improvement, showing comparable efficacy to nintedanib. Mechanistic studies revealed that DC591017 exerted anti-fibrotic effects by directly inhibiting fibroblasts activation and migration, and suppressing epithelial-mesenchymal transition (EMT). Besides its classical pharmacological action on macrophage function, DC591017 also inhibited Alternatively activated (M2) macrophages polarization and decreased dendritic cell infiltration. Lung-on-a-chip models further demonstrated that DC591017 alleviated fibrosis by modulating macrophages–fibroblasts–epithelial cells interactions. Conclusion As a novel PDE4 inhibitor, DC