Nrf2 attenuates inflammatory response in COPD/emphysema: Crosstalk with Wnt3a/β‐catenin and AMPK pathways

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation and abnormal inflammatory response. Wnt/β‐catenin and AMP‐activated protein kinase (AMPK) have been shown to modulate lung inflammatory responses and injury. However, it remains elusive whether Wnt/β‐catenin and AMPK modulate nuclear factor erythroid‐2 related factor‐2 (Nrf2)‐mediated protective responses during the development of emphysema. Here we showed that treatment with a Wnt pathway activator (LiCl) reduced elastase‐induced airspace enlargement and cigarette smoke extract (CSE)‐induced lung inflammatory responses in WT mice, which was associated with increased activation of Nrf2 pathway. Interestingly, these effects of LiCl were not observed in Nrf2−/− mice exposed to elastase. In normal human bronchial epithelial (NHBE) cells, Wnt3a overexpression up‐regulated, whereas Wnt3a knockdown further down‐regulated the levels of Nrf2 and its target proteins heme oxygenase‐1 (HO‐1) and NAD(P)H: quinone oxidoreductase 1 (NQO1) by CSE treatment. In contrast, Nrf2 deficiency did not have any effects on Wnt/β‐catenin pathway in mouse lungs and NHBE cells. Both elastase and CSE exposures reduced AMPK phosphorylation. A specific AMPK activator metformin increased Wnt3a, β‐catenin, Nrf2 phosphorylation and activation but reduced the levels of IL‐6 and IL‐8 in NHBE cells and mouse lungs exposed to CSE. Furthermore, Nrf2 deficiency abolished the protection of metformin against CSE‐induced increase in IL‐6 and IL‐8 in NHBE cells. In conclusion, Nrf2 mediates the protective effects of both Wnt3a/β‐catenin and AMPK on lung inflammatory responses during the development of COPD/emphysema. These findings provide potential therapeutic targets for the intervention of COPD/emphysema.

Tetraspanin 1 as a mediator of fibrosis inhibits EMT process and Smad2/3 and beta‐catenin pathway in human pulmonary fibrosis

“…35 Previous studies have indicated the TGF-β 1 signals-Smad2, β-catenin signalling axis activate EMT and α-SMA. 11,36 To explore the mechanism, the underlying TSPAN1-mediated the EMT in lung epithelial cells, we further assumed that the action of TSPAN1 on EMT is involved in activating Smad2/3 and the beta-catenin pathway, as shown in Figure 5, knockdown TSPAN1 promoted the phosphorylation of Smad2/3, but reduced the accumulation of beta-catenin ( Figure 5A,D), indicating the TM protein has a different action for profibrosis signalling pathways, even opposite action based on the TSPAN1 alone or combined with other proteins and the exogenous expression of TSPAN1-blocked TGF-β 1 -induced the phosphorylation of Smad2/3 and the accumulation of beta-catenin in A549 and ATII cells ( Figure 5F-I). These results showed that TSPAN1 modulated the TGF-β/Smad2/3 and beta-catenin signalling pathway in A549 and ATII cells.…”

Identification of novel differentially methylated sites with potential as clinical predictors of impaired respiratory function and COPD

“…24 SIAH2 upregulation mediates the ubiquitination of NRF2 which has been previously associated with respiratory function 25 and COPD. 26 Functional annotation of differently methylated genes identified enrichment of the molecular function alternative splicing (appendix p43). This finding is consistent with earlier reports that genes associated with COPD (unlike those associated with other complex traits examined) have greater transcriptional complexity due to a disproportionately high level of alternative splicing.…”

Characterizing Pharmacokinetic–Pharmacodynamic Relationships and Efficacy of PI3Kδ Inhibitors in Respiratory Models of TH2 and TH1 Inflammation

“…Although we did not currently study the impact of coadministration of PI3Kd inhibitors with other respiratory drugs, we believe that target engagement experiments (such as presented in this work) can be the basis of future explorations. From our point of view, this can be expanded to potential novel respiratory targets such as NOX4 and Nrf2 (Zhao et al, 2015;Zhou et al, 2016;Cui et al, 2018).…”