Potential therapeutic effect of oxygen-ozone in controlling of COVID-19 disease

Abstract

Atmospheric ozone is produced when nitrogen oxides react with volatile organic compounds. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome contains a unique N-terminal fragment in the Spike protein, which allows it to bind to air pollutants in the environment. 'Our approach in this review is to study ozone and its effect on the SARS-CoV-2 virus and patients with coronavirus disease 2019 (COVID-19). Article data were collected from PubMed, Scopus, and Google Scholar databases. Ozone therapy has antiviral properties, improves blood flow, facilitates the transfer of oxygen in hypoxemic tissues, and reduces blood coagulation phenomena in COVID-19 patients. Ozone has immunomodulatory effects by modulating cytokines (reduction of interleukin-1, interleukin-6, tumor necrosis factor-α, and interleukin-10), induction of interferon-γ, anti-inflammatory properties by modulating NOD-, LRR- and pyrin domain-containing protein 3, inhibition of cytokine storm (blocking nuclear factor-κB and stimulating nuclear factor erythroid 2-related factor 2 pathway), stimulates cellular/humoral immunity/phagocytic function and blocks angiotensin-converting enzyme 2. In direct oxygen-ozone injection, oxygen reacts with several biological molecules such as thiol groups in albumin to form ozonoids. Intravenous injection of ozonated saline significantly increases the length of time a person can remain hypoxic. The rectal ozone protocol is rectal ozone insufflation, resulting in clinical improvement in oxygen saturation and biochemical improvement (fibrinogen, D-dimer, urea, ferritin, LDH, interleukin-6, and C-reactive protein). In general, many studies have shown the positive effect of ozone therapy as a complementary therapy in the recovery of COVID-19 patients. All the findings indicate that systemic ozone therapy is nontoxic and has no side effects in these patients.

Keywords: COVID-19; MERS; SARS; SARS-CoV-2; coronavirus; immunity; ozone.

Figure 1

Proposed therapeutic effects of O₃ therapy for the treatment of COVID-19. Note: COVID-19 serves as an ACE2 receptor to enter into human respiratory epithelial cells through its Spike proteins. The transcription factor Nrf2 bound to Keep-1 activated by alkenals. The released Nrf2 translocates into the nucleus and, after binding to Maf, docks on ARE and activates several genes leading to the synthesis of antioxidant proteins. O₃ can inhibit apoptosis and degradation of the cartilage matrix by inhibiting the activation of NF-κB resulting in cell survival. O3 has immunomodulatory effects by anti-inflammatory properties by modulating NLRP3, inhibition of cytokine storm (reduction of IL-1β, IL-6, TNF-α, IFN-γ, IL-18, IL-12, GM-CSF), O₃ can stimulate cellular and humoral immunity through secondary messengers (H2O2) and NFAT/AP-1 signaling pathway. O₃ is a multifunctional drug that can stimulate inflammatory cytokines (IL-1β, IL-6, IFN-γ, TNF-α), anti-inflammatory cytokines (IL-4, IL-10). Biological responses to Nrf2/ARE activation with mild OT oxidative stress increase the levels of direct antioxidants such as GSH, CO, and bilirubin through glutathione and thioredoxin reductase. O₃ can reduce biomarkers such as CRP, ESR, and uric acid, which have been shown to reduce CRP in patients with COVID-19. O₃ increases oxygenation to the blood and tissues prevents the formation of small thrombosis by secretion of some prostacyclins such as PGI2. O₃ increases the expression of HO-1 in endothelial cells, stimulates 2–3 diphosphoglycerates, so more oxygen to the delivered tissues in COVID-19 patients. O₃ or its mediators (ozonides [ROS, LOPs]) are capable of oxidizing cysteine and tryptophan residues on S-spike protein and preventing their binding to the ACE2. O₂-O₃ also affects NO and iNOS signaling pathways. NO, especially by inhibiting palmitoylation of S protein, reduces the viral replication of COVID-19, thus preventing the virus from binding to the ACE2 receptor. ACE2: Angiotensin-converting enzyme 2; AP-1: activating protein-1; ARE: antioxidant response element; CO: carbon monoxide; COVID-19: coronavirus disease 2019; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; GM-CSF: granulocyte-macrophage colony-stimulating factor; GSH: glutathione; H₂O₂: hydrogen peroxide; HO-1: heme oxygenase-1; IFN-γ: interferon-γ; IL: interleukin; iNOS: inducible nitric oxide synthase; Keep-1: Kelch like-ECH-associated protein 1; LOP: lipid ozonation product; Maf: musculoaponeurotic fibrosarcoma; NFAT: nuclear factor of activated T-cells; NF-κB: nuclear factor-κB; NLRP3: NOD-, LRR- and pyrin domain-containing protein 3; NO: nitric oxide; Nrf2: nuclear factor erythroid 2-related factor 2; O₂: oxygen; O₃: ozone; OT: ozone therapy; PGI2: prostaglandin I2; ROS: reactive oxygen species; TNF-α: tomur necrosis factor-α.