Metformin attenuates lung fibrosis development via NOX4 suppression

Area of Science:

• Pulmonary Medicine
• Cell Biology
• Pharmacology

Background:

• Idiopathic pulmonary fibrosis (IPF) pathogenesis involves myofibroblast accumulation in fibroblastic foci (FF).
• Transforming growth factor-beta (TGF-β) is a key regulator of myofibroblast differentiation.
• Reactive oxygen species (ROS) are implicated in TGF-β-induced myofibroblast differentiation.

Purpose of the Study:

• To investigate the inhibitory role of metformin in lung fibrosis development.
• To explore metformin's modulation of TGF-β signaling pathways.
• To assess metformin's potential as an anti-fibrotic treatment for IPF.

Main Methods:

• In vitro studies using TGF-β-induced myofibroblast differentiation in lung fibroblasts (LF).
• In vivo examination of metformin's anti-fibrotic effects in a bleomycin (BLM)-induced lung fibrosis model.
• Assessment of AMP-activated protein kinase (AMPK) activation, NOX4 expression, ROS generation, and SMAD phosphorylation.

Main Results:

• Metformin treatment inhibited TGF-β-induced myofibroblast differentiation in LF via AMPK activation.
• Metformin reduced NOX4 expression and subsequent NOX4-derived ROS generation, crucial for TGF-β-induced SMAD phosphorylation.
• Metformin effectively inhibited BLM-induced lung fibrosis, NOX4 expression, and SMAD phosphorylation, with increased NOX4 observed in IPF lungs.

Conclusions:

• Metformin demonstrates a significant inhibitory effect on lung fibrosis development.
• The mechanism involves modulating TGF-β signaling through AMPK activation and reducing NOX4-derived ROS.
• Metformin presents a promising therapeutic strategy for treating IPF.