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

Abstract

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 ( NQO 1) 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.