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

W Cui, Z Zhang, P Zhang, J Qu, C Zheng… - Journal of Cellular …, 2018 - Wiley Online Library
W Cui, Z Zhang, P Zhang, J Qu, C Zheng, X Mo, W Zhou, L Xu, H Yao, J Gao
Journal of Cellular and Molecular Medicine, 2018Wiley Online Library
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 …
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.
Wiley Online Library