Modulating MiR-350/Akt/mTOR/beclin1 signaling by nitazoxanide ameliorates bleomycin-induced pulmonary fibrosis in a wistar rat model.

Abstract

AIMS: Pulmonary fibrosis (PF) is a destructive, inflammatory intersectional lung disease that has lethal consequences. Autophagy, a cellular homeostasis sustaining system, has shown a vital function in PF progression. Nitazoxanide (NTZ) is a broad-spectrum antiprotozoal agent that exhibits anti-inflammatory, antiviral, and anti-fibrotic properties. This study explores the potential therapeutic effect of NTZ on bleomycin (BLM)-induced PF in rats and studies its impact on autophagy pathways. MATERIALS AND METHODS: Four groups of adult male Wistar rats: the control group, BLM group (intratracheal single dose of 5 mg/kg), BLM + NTZ (200 mg/kg/day, p.o., for 28 days) group, and BLM + wortmannin (WM) (15 μg/kg/day, i.v., for 28 days) group, where WM was used to validate the role of PI3K/Akt/mTOR signaling pathway in PF. KEY FINDINGS: BLM administration promoted extensive degenerative changes and distortion of lung architecture that were reversed by NTZ. BLM upregulated the miR-350, PI3K/Akt/mTOR pathway, transforming growth factor-β1 (TGF-β1), and Smad3 while reducing autophagy-related proteins; beclin1 and LC3B, and the anti-inflammatory interleukin-37 (IL-37) relative to the control group. BLM induced tissue inflammation and apoptosis, and increased TNF-α, IL-6, and caspase-3 relative to the control group. NTZ significantly alleviated BLM-induced collagen fiber deposition and PF, suppressed miR-350/Akt/mTOR signaling, TGF-β1, IL-6, TNF-α, caspase-3 expressions, upregulated IL-37, and elevated autophagy-related proteins relative to the BLM group. SIGNIFICANCE: This study demonstrates, for the first time, the potential role of miR-350 in PF, and reveals a potential therapeutic role for NTZ in ameliorating BLM-induced PF, presumably by modifying the miR-350/Akt/mTOR/beclin1 signaling.