Insights on the mechanisms of action of ozone in the medical therapy against COVID-19

Abstract

An increasing amount of reports in the literature is showing that medical ozone (O₃) is used, with encouraging results, in treating COVID-19 patients, optimizing pain and symptoms relief, respiratory parameters, inflammatory and coagulation markers and the overall health status, so reducing significantly how much time patients underwent hospitalization and intensive care. To date, aside from mechanisms taking into account the ability of O₃ to activate a rapid oxidative stress response, by up-regulating antioxidant and scavenging enzymes, no sound hypothesis was addressed to attempt a synopsis of how O₃ should act on COVID-19. The knowledge on how O₃ works on inflammation and thrombosis mechanisms is of the utmost importance to make physicians endowed with new guns against SARS-CoV2 pandemic. This review tries to address this issue, so to expand the debate in the scientific community.

Keywords: Anti-inflammatory; Anti-oxidant; COVID-19; Medical therapy; Ozone therapy; Review.

Fig. 1

Cartoon showing the major pathways targeted by O₃ and its ROS and RES mediators on COVID-19. 1) O₃ can even enter the cell via aryl-hydrocarbon receptors (AHR) and may form ROS or RES, both able to activate the Nrf2/Keap1/ARE system, inducing an anti-oxidant response. As the activation of Nrf2 blocks the NF-κB signaling, Nrf2 activation inhibits the inflammatory signal (anti-inflammatory action). 2) The anti-oxidant response is enhanced by blocking the Keap-1 mediated degradation of Nrf2; 3) The activation of Nrf2 releases HO-1, which exerts an anti-thrombotic action and moreover inhibits p65 expression and translocation into the nucleus, so suppressing the NF-κB pathway (anti-inflammatory action); 4) the HO-1 mediated anti-thrombotic action promotes the reduction of organ damage in I/R injury models, which are protected by the HO-1 stabilized HIF-1α,. Nitric oxide (NO), elicited by the anti-thrombotic action, increases the production of HO-1, so emphasizing the beneficial effect of HO-1 on vascular endothelia, dampening thrombotic mechanisms and promoting cardiovascular protection. 5) Hypoxia induces the activation of the HIF-1α pathway, which up-regulating the expression of ACE-1 receptors and subsequently down-regulating ACE2R, inhibits SARS-CoV2 spreading in the organism. HIF-1α enhances the production of HO-1. Green circles (+) = activation, red circles (-) = inhibition. Ozone is indicated by the picture with 3 full circles.