Activation of nuclear factor erythroid 2-related (Nrf2) system as a novel therapeutic approach in COPD

Abstract

Background: Chronic Obstructive Pulmonary Disease (COPD) is an inflammatory lung disease caused by chronic exposure to cigarette smoke. Oxidative stress is one of the most important mechanisms involved in the physiopathology of COPD. Nuclear Factor Erythroid 2-related (Nrf2) is critical in protection against oxidative stress by inducing expression of antioxidant genes and a decrease in its expression has been observed in COPD patients.Objective: The aim of this study was to characterise the effects of Bardoxolone, Omavexolone and Obacunone as antioxidant drugs in COPD.Methods: Peripheral blood neutrophils from COPD and healthy volunteers and Primary Human Bronchial Epithelial cells were incubated with the cited drugs and stimulated with cigarette smoke extract (CSE). Expression of antioxidant genes, cytokine release, GSH levels and apoptosis were measured by RT-PCR, ELISA, luminescent assay and flow cytometry, respectively.Results: Expression assays using neutrophils, as well as lung tissue, showed a negative correlation between the expression of antioxidant genes and the severity of the disease. After stimulation with CSE and drug treatment, cells displayed an increase in expression of antioxidant genes, as well as, an inhibition in the release of inflammatory cytokines. In addition, GSH assays showed that Bardoxolone, Omavexolone and Obacunone were able to activate Nrf2 with EC50 values of 6.4nM, 15.3nM and 38.7μM, respectively. Moreover, these drugs were effective in apoptosis inhibition.Conclusions: Bardoxolone, Omavexolone and Obacunone show a huge antioxidant response against CSE-induced COPD by Nrf2 activation. Thus, these drugs may represent a promising therapeutic option in COPD.Footnotes Cite this article as: European Respiratory Journal 2019; 54: Suppl. 63, PA4216.This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at [www.ers-education.org][1] (ERS member access only). [1]: http://www.ers-education.org