2,5-Dimethylcelecoxib inhibits lung fibrosis in a mouse model of bleomycin-induced pulmonary fibrosis.

BACKGROUND

Idiopathic pulmonary fibrosis (IPF) is a progressive, incurable chronic lung disease characterized by irreversible fibrotic destruction. Current anti-fibrotic therapies are limited by adverse effects and high costs, necessitating more accessible treatments. Myofibroblasts, primarily derived from fibroblast-to-myofibroblast transition (FMT), drive IPF pathogenesis through excessive extracellular matrix (ECM) deposition. We previously reported that 2,5-dimethylcelecoxib (DM-C), a celecoxib derivative, exhibits anti-fibrotic effects in cardiac fibrosis by suppressing FMT. This study investigated the therapeutic effects of DM-C on pulmonary fibrosis in a bleomycin (BLM)-induced mouse model.

METHODS

Mice were intratracheally instilled with BLM and fed a diet containing 1000 ppm DM-C or vehicle, starting 3 days pre-instillation. On day 14, pulmonary fibrosis and bronchoalveolar lavage fluid (BALF) were evaluated. Inflammatory gene expression (Il6 and Ccl2) was assessed on day 7. Myofibroblast marker α-smooth muscle actin (α-SMA) expression was analyzed by in situ hybridization, and ECM proteins by Western blotting. In vitro, WI-38 human lung fibroblasts were used to assess DM-C's effect on transforming growth factor-β1 (TGF-β1)-induced FMT.

RESULTS

DM-C significantly attenuated pulmonary fibrosis formation and suppressed α-SMA expression and ECM protein production in the lung. DM-C did not reduce inflammatory cell infiltration in BALF or cytokine expression in lung tissues. In vitro, DM-C dose-dependently suppressed the TGF-β1-induced increase in α-SMA and ECM protein expression and Picrosirius red-positive collagen deposition. Mechanistically, DM-C inhibited the TGF-β/Smad and Wnt/β-catenin signaling pathways.

CONCLUSIONS

DM-C mitigates pulmonary fibrosis by inhibiting myofibroblast accumulation and ECM production through FMT suppression. DM-C represents a promising therapeutic candidate for IPF.