Geneticin ameliorates pulmonary fibrosis by attenuating the TGF-β/Smad via modulating AMPK/SIRT1 signaling

Aim: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive condition with unknown aetiology that causes the lung parenchyma to scar incessantly, lowering the quality of life and hastening death. In this investigation, we studied the anti-fibrotic activity of Geneticin (a derivative of gentamycin) using in vitro and in vivo models. Main methods: The TGF-beta-mediated differentiation model was adopted to investigate (fibrotic marker's levels/expression) the anti-fibrotic activity of geneticin (GNC) in in-vitro scenarios (LL29 and DHLF cells). In vivo, the bleomycin (BLM)-induced pulmonary fibrosis model was employed by administering BLM intratracheally. Post 14 days of BLM administration, animals were treated with geneticin (6.25, 12.5, and 25 mg center dot kg(-1)) for another 14 days, and their therapeutic effect was investigated using a spectrum of techniques. Key findings: RTqPCR and western-blot results revealed that geneticin treatment significantly attenuated the TGF-beta/BLM mediated fibrotic cascade of markers in both in-vitro and in-vivo models respectively. Further, the BLM-induced pulmonary fibrosis model revealed, that geneticin dose-dependently reduced the BLM-induced inflammatory cell infiltrations, and thickness of the alveoli walls, improved the structural distortion of the lung, and aided in improving the survival rate of the rats. Picrosirus and Masson's trichrome staining indicated that geneticin therapy reduced collagen deposition and, as a result, lung functional characteristics were improved as assessed by flexivent. Mechanistic studies have shown that geneticin reduced fibrosis by attenuating the TGF-beta/Smad through modulating the AMPK/SIRT1 signaling. Significance: These findings suggest that geneticin may be a promising therapeutic agent for the treatment of pulmonary fibrosis in clinical settings.