Acute respiratory distress syndrome (ARDS) caused by SARS-CoV-2 is largely the result of a dysregulated host response, followed by damage to alveolar cells and lung fibrosis. Exacerbated pro-inflammatory cytokines release (cytokine storm) and loss of T-lymphocytes (leucopenia) characterize the most aggressive presentation. Here we propose that a multi-faceted anti-inflammatory strategy based on pharmacological activation of nuclear factor erythroid 2 p45-related factor 2 (NRF2), can be deployed against the virus. The strategy provides robust cytoprotection by restoring the redox and protein homeostasis, promoting resolution of inflammation, and facilitating repair. NRF2 activators such as sulforaphane and bardoxolone methyl are already in clinical trials. The safety and efficacy information of these modulators in humans, together with their well-documented cytoprotective and anti-inflammatory effects in preclinical models, highlight the potential of this armamentarium for deployment to the battlefield against COVID-19.
The host inflammatory response is a critical determinant of disease outcome and correlates with disease severity in SARS-CoV-2-induced infection, for which there is no treatment to date.
Activation of transcription factor Nuclear factor erythroid 2 p45-Related Factor 2 (NRF2) promotes resolution of inflammation and in parallel, restores the cellular redox and protein homeostasis, and facilitates tissue repair.
NRF2 can be activated by pharmacological inducers that target Kelch-like ECH-associated protein 1 (KEAP1), the principal negative regulator of NRF2.
The available information on pharmacokinetics, pharmacodynamics, safety and efficacy for the NRF2 activators sulforaphane and bardoxolone methyl (currently in advanced clinical trials for other disease indications) in humans, makes them excellent candidates for testing in randomized clinical trials in COVID-19.