RESUMEN
BACKGROUND: Idiopathic pulmonary fibrosis is a lethal fibrosing interstitial pneumonia characterized by progressive worsening of dyspnea and lung function with poor prognosis. Since pirfenidone was approved for IPF treatment, the search for more effective candidates has been greatly intensified. METHODS: In this study, the antifibrotic effects and mechanisms of compound PBD-617, the ideal candidate discovered in our previous work, were investigated on transforming growth factor-ß1 (TGF-ß1)-induced human embryonic lung fibroblasts (HELF) and on bleomycin (BLM)-induced pulmonary fibrotic rats. RESULTS: Oral administration with PBD-617 decreased the levels of collagen I, collagen III and matrix metalloproteinase 7, and inhibited the protein expression of α-smooth muscle actin in BLM-induced pulmonary fibrosis rats. Furthermore, PBD-617 suppressed the expression of TGF-ß1, phosphorylated Smad3, phosphorylated p38 and activator protein 1 on TGF-ß1-induced HELF, while the regulation could be rescued by using p38 agonist p79350. CONCLUSION: PBD-617 not only inhibited TGF-ß1-induced HELF proliferation, but also attenuated BLM-induced pulmonary fibrosis in rats, with efficacy to some extent higher than that of pirfenidone at the same effective dosage. PBD-617 attenuated pulmonary fibrosis effectively by suppressing activation of TGF-ß1/Smad3 and p38 signaling pathways.