Pyrvinium Attenuates Amiodarone-Induced Pulmonary Fibrosis in Male Rats: Association with Modulation of Wnt/β-Catenin Related Proteins.

Abstract

Background/Objectives: Amiodarone (AmoD) is an effective antiarrhythmic drug whose use is limited by life-threatening pulmonary fibrosis. Although Wnt/β-catenin signaling contributes to several lung diseases, its involvement in AmoD-induced pulmonary fibrosis remains unknown. This study investigated whether Wnt/β-catenin signaling is altered during AmoD-induced pulmonary fibrosis and whether its pharmacological modulation with pyrvinium (Pyrv) attenuates this toxicity. Methods: Rats were allocated into four groups and treated for five weeks as follows: normal control, AmoD (30 mg/kg/day), Pyrv (60 µg/kg/day), and AmoD + Pyrv. Pulmonary injury and fibrosis were evaluated using histopathological examination, Masson's trichrome staining, immunohistochemical assessment of collagen I, α-smooth muscle actin (α-SMA), and transforming growth factor-β1 (TGF-β1), and measurement of inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and Th1/Th2-related cytokines. Wnt/β-catenin-associated proteins, including Wnt3a, active β-catenin, and glycogen synthase kinase-3β (GSK-3β), were evaluated by Western blotting. Results: AmoD induced marked pulmonary architectural disruption, inflammatory cell infiltration, increased lung weight/body weight ratio, collagen deposition, and increased expression of TGF-β1, α-SMA, and collagen I, as well as increased levels of TNF-α, IL-6, and disruption of Th1/Th2 immune balance. At the molecular level, AmoD increased Wnt3a, active β-catenin, and the p-GSK-3β/total GSK-3β ratio. Co-administration of Pyrv significantly attenuated the histopathological, inflammatory, immune, and fibrotic alterations and reduced the AmoD-associated changes in Wnt/β-catenin-related proteins. Conclusions: The findings indicate that AmoD-induced pulmonary injury and fibrosis are associated with modulation of Wnt/β-catenin related proteins and that Pyrv treatment attenuates these pathological changes. Targeting this pathway could be a promising protective strategy to prevent fibrogenesis during AmoD treatment.