Abstract
Inflammation is a pathology implicated in a wide range of human diseases. Recent years have seen tremendous progress in developing new types of anti-inflammatory agents for the treatment of inflammation of various origins. However, each has its own strengths and weaknesses. The very fact that there needs to have multiple types of anti-inflammatory agents underlines the complexity of inflammatory diseases and conditions, their molecular origins, and their treatment. Such complexity dictates the need to search for new approaches with improved potency and efficacy as well as reduced side effects. For these reasons, we are interested in exploring the possibility of generating synergy between carbon monoxide (CO), an endogenously produced cytoprotective agent, and known anti-inflammatory agents. Herein, we report the potentiating actions of CO on the anti-inflammatory effects of cortisone and dexamethasone as demonstrated in their ability to suppress the expression of TNF-α and IL-6 induced by either LPS or the S protein of SARS-CoV-2. Such effects are reflected in the substantially increased potency as well efficacy, when the efficacy of the corticosteroid alone does not allow for complete suppression of the expression of these cytokines. Further, increased attenuation of p65 phosphorylation is at least part of the molecular mechanism for the observed potentiating effects. We hope our work will stimulate a high level of activity along the same direction, leading to anti-inflammatory strategies with improved potency and efficacy and reduced side effects.