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Med Hypotheses ; 146: 110394, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-919589


No definitive treatment for COVID-19 exists although promising results have been reported with remdesivir and glucocorticoids. Short of a truly effective preventive or curative vaccine against SARS-CoV-2, it is becoming increasingly clear that multiple pathophysiologic processes seen with COVID-19 as well as SARS-CoV-2 itself should be targeted. Because alpha-1-antitrypsin (AAT) embraces a panoply of biologic activities that may antagonize several pathophysiologic mechanisms induced by SARS-CoV-2, we hypothesize that this naturally occurring molecule is a promising agent to ameliorate COVID-19. We posit at least seven different mechanisms by which AAT may alleviate COVID-19. First, AAT is a serine protease inhibitor (SERPIN) shown to inhibit TMPRSS-2, the host serine protease that cleaves the spike protein of SARS-CoV-2, a necessary preparatory step for the virus to bind its cell surface receptor ACE2 to gain intracellular entry. Second, AAT has anti-viral activity against other RNA viruses HIV and influenza as well as induces autophagy, a known host effector mechanism against MERS-CoV, a related coronavirus that causes the Middle East Respiratory Syndrome. Third, AAT has potent anti-inflammatory properties, in part through inhibiting both nuclear factor-kappa B (NFκB) activation and ADAM17 (also known as tumor necrosis factor-alpha converting enzyme), and thus may dampen the hyper-inflammatory response of COVID-19. Fourth, AAT inhibits neutrophil elastase, a serine protease that helps recruit potentially injurious neutrophils and implicated in acute lung injury. AAT inhibition of ADAM17 also prevents shedding of ACE2 and hence may preserve ACE2 inhibition of bradykinin, reducing the ability of bradykinin to cause a capillary leak in COVID-19. Fifth, AAT inhibits thrombin, and venous thromboembolism and in situ microthrombi and macrothrombi are increasingly implicated in COVID-19. Sixth, AAT inhibition of elastase can antagonize the formation of neutrophil extracellular traps (NETs), a complex extracellular structure comprised of neutrophil-derived DNA, histones, and proteases, and implicated in the immunothrombosis of COVID-19; indeed, AAT has been shown to change the shape and adherence of non-COVID-19-related NETs. Seventh, AAT inhibition of endothelial cell apoptosis may limit the endothelial injury linked to severe COVID-19-associated acute lung injury, multi-organ dysfunction, and pre-eclampsia-like syndrome seen in gravid women. Furthermore, because both NETs formation and the presence of anti-phospholipid antibodies are increased in both COVID-19 and non-COVID pre-eclampsia, it suggests a similar vascular pathogenesis in both disorders. As a final point, AAT has an excellent safety profile when administered to patients with AAT deficiency and is dosed intravenously once weekly but also comes in an inhaled preparation. Thus, AAT is an appealing drug candidate to treat COVID-19 and should be studied.

COVID-19/drug therapy , Models, Biological , alpha 1-Antitrypsin/therapeutic use , Acute Lung Injury/drug therapy , Anti-Inflammatory Agents/therapeutic use , Antithrombins/therapeutic use , Antiviral Agents/therapeutic use , Apoptosis/drug effects , COVID-19/physiopathology , Extracellular Traps/drug effects , Host Microbial Interactions/drug effects , Host Microbial Interactions/physiology , Humans , Leukocyte Elastase/antagonists & inhibitors , Pandemics , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Serine Endopeptidases/drug effects , Serine Endopeptidases/physiology , Virus Internalization/drug effects , alpha 1-Antitrypsin/administration & dosage
J Clin Med ; 9(9)2020 Sep 11.
Article in English | MEDLINE | ID: covidwho-892446


Understanding of the pathogenesis of the coronavirus disease-2019 (COVID-19) remains incomplete, particularly in respect to the multi-organ dysfunction it may cause. We were the first to report the analogous biological and physiological features of COVID-19 pathogenesis and the harmful amplification loop between inflammation and tissue damage induced by the dysregulation of neutrophil extracellular traps (NETs) formation. Given the rapid evolution of this disease, the nature of its symptoms, and its potential lethality, we hypothesize that COVID-19 progresses under just such an amplifier loop, leading to a massive, uncontrolled inflammation process. Here, we describe in-depth the correlations of COVID-19 symptoms and biological features with those where uncontrolled NET formation is implicated in various sterile or infectious diseases. General clinical conditions, as well as numerous pathological and biological features, are analogous with NETs deleterious effects. Among NETs by-products implicated in COVID-19 pathogenesis, one of the most significant appears to be elastase, in accelerating virus entry and inducing hypertension, thrombosis and vasculitis. We postulate that severe acute respiratory syndrome-coronavirus 2 (SARS-CoV2) may evade innate immune response, causing uncontrolled NETs formation and multi-organ failure. In addition, we point to indicators that NETS-associated diseases are COVID-19 risk factors. Acknowledging that neutrophils are the principal origin of extracellular and circulating DNA release, we nonetheless, explain why targeting NETs rather than neutrophils themselves may in practice be a better strategy. This paper also offers an in-depth review of NET formation, function and pathogenic dysregulation, as well as of current and prospective future therapies to control NETopathies. As such, it enables us also to suggest new therapeutic strategies to fight COVID-19. In combination with or independent of the latest tested approaches, we propose the evaluation, in the short term, of treatments with DNase-1, with the anti-diabetic Metformin, or with drugs targeting elastase (i.e., Silvelestat). With a longer perspective, we also advocate a significant increase in research on the development of toll-like receptors (TLR) and C-type lectin-like receptors (CLEC) inhibitors, NET-inhibitory peptides, and on anti-IL-26 therapies.