Therapeutic use of fisetin and pirfenidone combination in bleomycin-induced pulmonary fibrosis in adult male albino rats

Pulmonary fibrosis is an important health problem; one of the drugs used in its treatment is pirfenidone (PFD). Fisetin (FST) is a flavonoid with antioxidative, anti-inflammatory, and antifibrotic effects. The aim of this study was to induce PF in rats with bleomycin (BLM) and to investigate the combined effect of PFD and FST in the treatment of fibrosis. In the study, 40 male Wistar rats were divided into five groups (n = 8). Sham group was administered saline on day 0 and BLM (5 mg/kg, i.t.) was administered to the other groups; BLM + PFD group: PFD (50 mg/kg) was administered every day between the first and 15th days; BLM + FST group: FST (25 mg/kg) was administered between the first and 15th days; BLM + PFD + FST group: PFD (50 mg/kg) and FST (25 mg/kg) were administered by gavage every day between the first and 15th days. At the end of the 15th day, BAL was performed under anaesthesia and lung tissues were removed. Histopathological, biochemical, and RT-PCR analyses were performed in the lung tissue. In our study, the concomitant use of FST and PFD caused downregulation of NF-kappa B p65, TGF-beta 1, and alpha-SMA expressions; downregulation of TIMP-1, MMP-2, and MMP-9 genes; downregulation of HYP, MPO, and MDA activity; decrease in the number of differential cells in BAL; and upregulation of GSH. This shows that FST and PFD have antifibrotic, antioxidative, and anti-inflammatory effects. Our results show that the combined use of PFD and FST in BLM-induced pulmonary fibrosis reduces extracellular matrix accumulation, downregulates the level of gelatinases and their inhibitors, and provides significant improvements in antioxidative defence parameters.