Immunity

COVID-19-related pulmonary damage is caused by oxidative stress and lipid oxidation. Notably, Virus-induced uncontrolled oxidant species generation in monocytes/macrophages causes the production of oxidized phospholipids (Ox-PLs) especially from lung surfactants, containing 80-90% phospholipids including unsaturated phosphatidylcholine as oxidizable substrate. Aptly, OxPLs has the potential to activate the macrophage Toll-like receptor 4 (TLR4) signaling cascade, causing cytokine overproduction and acute lung injury (ALI) finally peaking in acute respiratory distress syndrome (ARDS). 

Thus, a fundamental aspect of antioxidant therapy in COVID-19 remains the timing of antioxidant administration and that the antioxidant must see its administration in the early course of the disease, ideally before the development of pneumonia, to prevent oxidant-induced OxPLs formation and TLR4 activation. 

A report by de Alencar et al. describes the therapeutic effects of N-acetylcysteine (NAC) in patients with severe COVID-19 illustrating that intravenous NAC, a well-known hydrophilic thiol antioxidant, was clinically ineffective compared to placebo. The selection of patients and the type of antioxidant used in this study remains debatable. The enrolled patients for the study were already suffering from a severe form of COVID-19 with evident pneumonia that does not desire only antioxidant treatment. 

After intravenous administration of NAC, it undergoes extensive reaction with plasma and tissue proteins, thus extensively limiting the amount of circulating free drug for its direct antioxidant effects. The lipophilic liposomal formulation of NAC is superior to conventional NAC with a better pharmacokinetic-pharmacodynamic profile. There remains experimental evidence proving liposomal NAC, but not conventional NAC, can render significant protection against lipopolysaccharide-induced ALI reaching far higher lung concentrations. 

Lipophilic antioxidants are important because of their inherited property of directly protect lung surfactants and cell membrane phospholipids against Accepted Manuscript 3 oxidative injury. This is true for vitamin E (V-E), α-tocopherol, the most important lipophilic antioxidant in the lung and an integral constituent of alveolar surfactant. V-E administration is known to inhibit experimentally-induced ALI and improve APACHE II score in ARDS patients. It functions as an efficient radical scavenger in the lipid phase; as a result, V-E is converted into a radical species, namely α-tocopheroxyl radical that can be further oxidized into αtocopheroxyl quinone or reduced back to V-E by reducing compounds with V-E regeneration. 

Ascorbic acid (AA), a potent antioxidant, can reduce α-tocopheroxyl radicals to V-E undergoing oxidation to dehydroascorbic acid; this latter is in turn readily reduced for example by dihydrolipoic acid (DHLA) in the couple lipoic acid/DHLA, so that the association of V-E, AA and DHLA is markedly effective contrary to lipid oxidation. 

α-tocopheroxyl radicals are reduced directly and efficiently to V-E also by the lipophilic antioxidant ubiquinol, sparing thiols. 

Thus the aforementioned antioxidants may be incorporated into liposomes, in turn, prepared using also plasmalogens, ether phospholipids with antioxidant properties present in lung surfactants. Inhalational administration of liposomal antioxidants further maximizes pulmonary therapeutic effects than nebulized liposomal antibiotics. It is thus essential to carry out further investigations with this specific antioxidant therapy for the early treatment of COVID-19.