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.

Keywords: Nrf2; Nrf2–Keap1 pathway; asthma; inflammation; molecular mechanism; oxidative stress; respiratory disease.

FIGURE 1

Involvement of Nrf2 in ARDS in humans and in vivo models. In humans, the risk of developing an ARDS during severe trauma is associated with the possession of a functional promoter that has affected the binding affinity to a promoter site upstream of the Nrf2 gene. Induction of hyperoxia-induced ARDS in NRf2-deficient mice is associated with increased lung inflammation and capillary permeability. Conversely, in a LPS induced ARDS model, induction of Nrf2 is associated with a decrease in mortality and inflammation, notably via the M2 polarization of macrophages. ↑, Increase; ↓, Decrease; block; *, compared to wild type mice or healthy subjects; **, compared to un- treated mice; , macrophages; WT, wild type.

FIGURE 2

Involvement of Nrf2 in COPD in human and in experimental models. In smokers with emphysema, the nuclear localization of Nrf2 is decreased in macrophages as well as the anti-oxidant response. This altered antioxidant response is inversely correlated with airflow obstruction. In Nrf2 deficient mice, CSE or pancreatic elastase intra-tracheal instillations evoke a decreased antioxidant response and an increase emphysema. In Nrf2-deficient mice, CSE or intra-tracheal instillation of pancreatic elastase results in a decreased antioxidant response and increased emphysema compared to wild type mice. Upregulation of Nrf2 by physical activity, LiCl or Nrf2 inducers reduces the induction of cigarette smoke-induced emphysema. ↑, Increase; ↓, Decrease; , block; *, compared to wild type mice or healthy subject; **, compared to non treated mice; , macrophages; , Cigarette smoke; WT, wild type; PPE, porcine pancreatic elastase; WT, wild type; LiCl, lithium chloride.

FIGURE 3

Involvement of Nrf2 in IPF in humans and in experimental models. In IPF, Nrf2 expression varies between cells: increased in type II pneumocytes and reduced in fibroblasts and fibroblast foci. In a bleomycin-induced pulmonary fibrosis model, Nrf2-deficient mice exhibit more severe pulmonary fibrosis, increased TGFβ and pulmonary inflammation compared to wild type mice. Downregulation of Nrf2 in fibroblasts induces myofibroblast differentiation. A Nrf2 inducer can inhibit this process. ↑, Increase; ↓, Decrease; , block; , exposure; *, compared to wild type mice or healthy subjects; KD, knock-down; WT, wild type.

FIGURE 4

Involvement of Nrf2 in asthma in humans and in experimental models. The administration of foods rich in sulforaphane (broccoli sprouts) in atopic asthmatic subjects increased plasma SFN concentration without any modification of the FeNO or of the antioxidant response. Induction of asthma in Nrf2-deficient mice is associated with increased airway hyperresponsiveness and inflammatory cell recruitment in BAL. Administration of an Nrf2 inducer restores the corticosteroid sensitivity of ovalbumin-induced asthma concomitantly exposed to cigarette smoke. ↑, Increase; ↓, Decrease; , reduce; , block; *, compared to wild type mice or healthy subjects; **, compared to non treated mice; DE, diesel exhaust; OVA, ovalbumin; AHR, airway hyperresponsiveness; SFN, sulforaphane; BS, broccoli sprouts; FeNO, fraction of exhaled nitric oxide; WT, wild type.