Add‐On Dextromethorphan Improves the Effects of Pirfenidone in Bleomycin‐Treated Mice and Patients With Pulmonary Fibrosis

ABSTRACT Background and Objective Idiopathic pulmonary fibrosis is a progressive interstitial lung disease characterised by excessive activation of myofibroblasts. However, currently available antifibrotic drugs exhibit limited efficacy. The dysregulation of redox processes plays a significant role in the pathogenesis of idiopathic pulmonary fibrosis. Dextromethorphan (DM) is used in the treatment of various inflammation‐related diseases. This study aimed to investigate the effectiveness of the combination of DM and pirfenidone (PFD) in treating idiopathic pulmonary fibrosis in both animal models and humans. Methods In a bleomycin‐induced pulmonary fibrosis mouse model, the anti‐fibrotic effects of DM and/or PFD were assessed by evaluating fibrotic area, hydroxyproline levels, and fibrotic markers. In a transforming growth factor‐β1‐induced cell model, proliferation, migration, fibrosis markers, and oxidative stress were analysed to elucidate the mechanisms underlying the anti‐fibrotic actions of DM and/or PFD. Finally, the efficacy of DM combined with PFD in patients with pulmonary fibrosis was evaluated by comparing pulmonary imaging scores and pulmonary function before and after treatment in the PFD group and the PFD + DM group. Results We observed that even ultralow doses of DM, either alone or in combination with PFD, demonstrated substantial protective effects in mice. Notably, administration of DM or combined drugs at 2 weeks after bleomycin modelling still showed anti‐fibrotic effects. In vitro, DM monotherapy and combination therapy restored the redox balance by suppressing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4/reactive oxygen species production and upregulating superoxide dismutase, contributing to their anti‐fibrotic mechanisms. In the clinical study, add‐on DM improved PFD in mitigating pulmonary function decline and improving chest high‐resolution computed tomography imaging scores. Conclusions Ultralow doses of dextromethorphan significantly alleviate pulmonary fibrosis in bleomycin‐treated mice through restoring the redox balance. Add‐on DM improves the effects of PFD in both bleomycin‐treated mice and patients with pulmonary fibrosis. Trial Registration: ChiCTR2000037602