An Update on the Role of Nrf2 in Respiratory Disease: Molecular Mechanisms and Therapeutic Approaches

Abstract

Nuclear factor erythroid 2-related factor (Nrf2) is a transcriptional activator of the cell protection gene that binds to the antioxidant response element (ARE). Therefore, Nrf2 protects cells and tissues from oxidative stress. Normally, Kelch-like ECH-associated protein 1 (Keap1) inhibits the activation of Nrf2 by binding to Nrf2 and contributes to Nrf2 break down by ubiquitin proteasomes. In moderate oxidative stress, Keap1 is inhibited, allowing Nrf2 to be translocated to the nucleus, which acts as an antioxidant. However, under unusually severe oxidative stress, the Keap1-Nrf2 mechanism becomes disrupted and results in cell and tissue damage. Oxide-containing atmospheric environment generally contributes to the development of respiratory diseases, possibly leading to the failure of the Keap1-Nrf2 pathway. Until now, several studies have identified changes in Keap1-Nrf2 signaling in models of respiratory diseases, such as acute respiratory distress syndrome (ARDS)/acute lung injury (ALI), chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and asthma. These studies have confirmed that several Nrf2 activators can alleviate symptoms of respiratory diseases. Thus, this review describes how the expression of Keap1-Nrf2 functions in different respiratory diseases and explains the protective effects of reversing this expression.

Obacunone alleviates ferroptosis during lipopolysaccharide-induced acute lung injury by upregulating Nrf2-dependent antioxidant responses

“…We further investigated the potential mechanisms underlying the effects of OB against LPS-induced ALI. Some studies have shown that Nrf2 is a signal coordinator, attenuating LPS-induced ALI by inhibiting inflammation and oxidative stress [ 40 ]. Under normal conditions, Nrf2 binds to Kelch-like ECH-associated protein 1 (Keap1), which is then ubiquitinated by a Cul3-based E3 ligase and degraded.…”

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

“…In keeping with its role as a transcription factor, Nrf2 activates the expression of factors involved in detoxifying ROS, such as glutamate-cysteine ligase catalytic subunit (GCLC), glutamate-cysteine ligase modifier subunit (GCLM), GPx, GR, heme-oxygenase (HO-1), Prx, and SOD3 [ 197 ]. Thus, activation of Nrf2 leads to an antioxidative response, which is generally associated with an improved outcome of lung injury in mouse models [ 198 ]. In line with this, Nrf2-deficient mice show enhanced acute lung injury compared to wild-type mice following intestinal ischemia/reperfusion [ 199 ].…”

Molecular hydrogen is a potential protective agent in the management of acute lung injury

“…The activation of Nrf2 signaling plays an essential role in preventing injury induced by oxidative stress to cells and tissues. The redox balance maintained by Nrf2 is important for the airways, and Nrf2 activation confers protective effects on various lung disorders including ALI/ARDS (Liu et al 2019;Lee et al 2021). Moreover, Nrf2 contributes to the regulation of the HO-1 axis and NF-κB pathway, both of which are potent anti-inflammatory targets.…”