The Role of Nrf2 in Pulmonary Fibrosis: Molecular Mechanisms and Treatment Approaches

Abstract

Pulmonary fibrosis is a chronic, progressive, incurable interstitial lung disease with high mortality after diagnosis and remains a global public health problem. Despite advances and breakthroughs in understanding the pathogenesis of pulmonary fibrosis, there are still no effective methods for the prevention and treatment of pulmonary fibrosis. The existing treatment options are imperfect, expensive, and have considerable limitations in effectiveness and safety. Hence, there is an urgent need to find novel therapeutic targets. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a central regulator of cellular antioxidative responses, inflammation, and restoration of redox balance. Accumulating reports reveal that Nrf2 activators exhibit potent antifibrosis effects and significantly attenuate pulmonary fibrosis in vivo and in vitro. This review summarizes the current Nrf2-related knowledge about the regulatory mechanism and potential therapies in the process of pulmonary fibrosis. Nrf2 orchestrates the activation of multiple protective genes that target inflammation, oxidative stress, fibroblast–myofibroblast differentiation (FMD), and epithelial–mesenchymal transition (EMT), and the mechanisms involve Nrf2 and its downstream antioxidant, Nrf2/HO−1/NQO1, Nrf2/NOX4, and Nrf2/GSH signaling pathway. We hope to indicate potential for Nrf2 system as a therapeutic target for pulmonary fibrosis.

Nrf-2 as a novel target in radiation induced lung injury

“…In the late stage of RILI, PF is a consequence of delayed radiation effects and is often considered an irreversible hazard [ 4 , 88 ]. Recent clinical studies have shown that Nrf-2 is associated with radiation-induced PF, and Nrf-2 activators have demonstrated anti-fibrotic effects [ 89 ]; this is mainly because Nrf-2 deficiency inhibits the mobilization of ΔNp63 stem/progenitor cells while amplifying the tendency of alveolar type 2 cells to convert into myofibroblasts under radiation induction [ 64 ]. In the injured lung, Δp63+/Krt5+ stem cells are significantly mobilized and proliferate.…”

Advances in the Use of N-Acetylcysteine in Chronic Respiratory Diseases

“…The loss of homeostasis between epithelial and mesenchymal cells and increased resistance of myofibroblasts to apoptosis may then result in the abundant fibroblast activation and accumulation of the extracellular matrix leading to pulmonary fibrosis [ 148 , 150 ]. The above-mentioned changes are associated with a significant oxidative-antioxidant imbalance and GSH deficiency [ 151 , 152 , 153 , 154 ]. Oxidative stress in pulmonary fibrosis is associated mainly with the NF-κB signaling pathway, the Kelch-like ECH-associated protein 1 (Keap1)/Nrf2/ARE pathway, and the NADPH oxidase (NOX)4-Nrf2 signaling cascade [ 155 ].…”

Vinpocetine alleviated alveolar epithelial cells injury in experimental pulmonary fibrosis by targeting PPAR-γ/NLRP3/NF-κB and TGF-β1/Smad2/3 pathways

“…This study will focus on some molecular targets, including Nuclear factor erythroid 2-related factor 2 (Nrf2), a regulatory nuclear factor that influences the activity and cellular response of the antioxidant system 17 , NF-κB, and the inflammasome NLRP3 which are closely related to one another and influence the level of inflammatory and pro-fibrotic cytokines in the microenvironment as well as the apoptosis and senescence of alveolar epithelial cells especially for NF-κB 18 . As for peroxisome proliferator-activated receptor gamma (PPAR-γ), studies have suggested its important role in modulating the inflammatory and fibrotic responses in the lung 19 .…”