The effects of Nrf2 activators and oxidative stress on COPD alveolar macrophages

Jian Li, James Baker, Clare Murray, Nicky Cooper, Cathy Lucas, Craig Fox, Dave Singh, Simon Lea

Research output: Chapter in Book/Report/Conference proceedingConference contributionpeer-review

Abstract

Nuclear factor erythroid-derived 2-like 2 (Nrf2) regulates cellular antioxidant defence in epithelial cells and alveolar macrophages (AM). Increased oxidative stress is linked to Nrf2 downregulation in lungs of chronic obstructive pulmonary disease (COPD) patients. Our aims were to assess levels of Nrf2 and its regulatory protein Keap1 in COPD compared to controls and test the effect of Nrf2 activators and oxidative stress on COPD AM

Methods: Lung resected tissue from 11 non-smokers(NS), 12 smokers(S) and 12 COPD patients were analysed for epithelial and AM expression of Nrf2 and Keap1. AM were isolated from lungs and Nrf2 and Keap1 expression assessed by qPCR (N=7 NS, 27 S and 29 COPD). AM were cultured with Nrf2 activators CDDO, C4X_6665 and GSK Compound 7 (0.3-1000nM) or MMF and Sulforafane (1-10μM) for 24h(N=8 S and 8 COPD). NQO1 activity and qPCR for expression of Nrf2 target genes NQO1 and HO1 were assessed. AM were also cultured under hypoxia (2% O2) and functional genes MARCO, CD206, CD36, CD80 and Nrf2, Keap1, NQO1 and HO1 were assessed

Results: Nrf2 and Keap1 expression levels were not altered in epithelium or AM of COPD patients compared to controls. Nrf2 activators CDDO, C4X_6665, GSK Compound 7, MMF and Sulforafane all showed dose-dependent induction of NQO1 and HO1 expression and NQO1 activity in AMs from both COPD and S. Hypoxic conditions reduced AM expression of all genes

Conclusion: Nrf2 expression was not altered in COPD epithelium or AM. Nrf2 and associated genes were down regulated by hypoxic conditions. Nrf2 activator compounds are pharmacologically active in COPD AM. Although not directly tested here, our results suggest that Nrf2 activation will provide protection against hypoxic stress
Original languageEnglish
Title of host publicationEuropean Respiratory Journal
Publication statusPublished - 7 Sept 2020

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