Role of Nrf2 in Disease: Novel Molecular Mechanisms and Therapeutic Approaches – Pulmonary Disease/Asthma

Abstract

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a major transcription factor involved in redox homeostasis and in the response induced by oxidative injury. Nrf2 is present in an inactive state in the cytoplasm of cells. Its activation by internal or external stimuli, such as infections or pollution, leads to the transcription of more than 500 elements through its binding to the antioxidant response element. The lungs are particularly susceptible to factors that generate oxidative stress such as infections, allergens and hyperoxia. Nrf2 has a crucial protective role against these ROS. Oxidative stress and subsequent activation of Nrf2 have been demonstrated in many human respiratory diseases affecting the airways, including asthma and chronic obstructive pulmonary disease (COPD), or the pulmonary parenchyma such as acute respiratory distress syndrome (ARDS) and pulmonary fibrosis. Several compounds, both naturally occurring and synthetic, have been identified as Nrf2 inducers and enhance the activation of Nrf2 and expression of Nrf2-dependent genes. These inducers have proven particularly effective at reducing the severity of the oxidative stress-driven lung injury in various animal models. In humans, these compounds offer promise as potential therapeutic strategies for the management of respiratory pathologies associated with oxidative stress but there is thus far little evidence of efficacy through human trials. The purpose of this review is to summarize the involvement of Nrf2 and its inducers in ARDS, COPD, asthma and lung fibrosis in both human and in experimental models.

Acid Sphingomyelinase Controls Early Phases of Skeletal Muscle Regeneration by Shaping the Macrophage Phenotype

“…The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and its signaling play a key role in protecting cells from oxidative stress and inflammation [ 60 , 61 , 62 , 63 ]. In this respect, the anti-inflammatory effect in the absence of ASMase was confirmed by the enhanced expression of Nrf2 ( Figure 4 D) and its downstream genes Heme oxygenase-1 (HO-1), Glutathione peroxidase 1 (GPX1) and Superoxide dismutase 3 (SOD3) ( Figure 4 E) in ASMase-KO mice following tissue damage.…”

“…That this event shapes a definite niche at the damaged site improving muscle regeneration was suggested by the concomitant increase of Insulin-like growth factor 1 (IGF-1) (Figure 4C), a potent enhancer of tissue regeneration [58,59]. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and its signaling play a key role in protecting cells from oxidative stress and inflammation [60][61][62][63]. In this respect, the anti-inflammatory effect in the absence of ASMase was confirmed by the enhanced expression of Nrf2 (Figure 4D) and its downstream genes Heme oxygenase-1 (HO-1), Glutathione peroxidase 1 (GPX1) and Superoxide dismutase 3 The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and its signaling play a key role in protecting cells from oxidative stress and inflammation [60][61][62][63].…”

“…The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and its signaling play a key role in protecting cells from oxidative stress and inflammation [60][61][62][63]. In this respect, the anti-inflammatory effect in the absence of ASMase was confirmed by the enhanced expression of Nrf2 (Figure 4D) and its downstream genes Heme oxygenase-1 (HO-1), Glutathione peroxidase 1 (GPX1) and Superoxide dismutase 3 The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and its signaling play a key role in protecting cells from oxidative stress and inflammation [60][61][62][63]. In this respect, the anti-inflammatory effect in the absence of ASMase was confirmed by the enhanced expression of Nrf2 (Figure 4D) and its downstream genes Heme oxygenase-1 (HO-1), Glutathione peroxidase 1 (GPX1) and Superoxide dismutase 3 (SOD3) (Figure 4E) in ASMase-KO mice following tissue damage.…”

Antioxidants as Therapeutic Agents in Acute Respiratory Distress Syndrome (ARDS) Treatment—From Mice to Men

“…The most important transcription factor in regulating antioxidant genes is the capand-collar type transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) [195]. Its expression is regulated under healthy conditions by Keap1, which targets Nrf2 for pro- Vitamin C has also been identified as an antioxidant with a protective function in murine acute lung injury [193].…”

Roles of NRF2 in Fibrotic Diseases: From Mechanisms to Therapeutic Approaches

“…Ureteral obstruction and hypoxia caused by renal ischemia lead to oxidative stress and even damage, which may be the mechanism accounting for the diseases above (Su et al, 2019). NRF2 is a wellknown factor that plays a prominent role in the hemostasis of oxidation and antioxidation by regulating the expression of the downstream proteins HO-1 and NQO1, for instance (Audousset et al, 2021). It is inferred that abnormal NRF2-related pathways participate in several oxidation injury-induced nephropathies, including CKD and renal fibrosis.…”