SARS-CoV-2 infecting endothelial cells, biochemical alterations, autopsy findings and outcomes in COVID-19, suggest role of hypoxia-inducible factor-1 Translated title: SARS-CoV-2 dovodi do infekcije endotelijelnih ćelija, menja biohemijske nalaze i nalazi autopsije ukazuju na ishod COVID-19 i ulogu hipoksija-inducibilnog faktora 1

Abstract

Researchers around the world have experienced the dual nature of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), 'tragically lethal in some people while surprisingly benign in others'. There have been congregating studies of the novel coronavirus disease (COVID-19), a disease that mainly attacks the lungs but also has mystifying effects on the heart, kidneys and brain. Researchers are also gathering information to ascertain why people are dying of COVID-19, whether it is solely a respiratory disorder, a coagulation disorder or multi-organ failure. Alterations in laboratory parameters like lactate, ferritin and albumin have been established as risk factors and are associated with outcomes, yet none have not been sub stantiated with a scientific biochemical rationale. SARSCoV-2 affects the alveolar type II epithelial cells which significantly disturbs its surfactant homeostasis, deprives Na,K-ATPase of ATP, thereby disturbing the alveolar lining fluid which then gradually decreases the alveolar gaseous exchange initiating the intracellular hypoxic conditions. This activates AMP-activated kinase, which further inhibits Na,K-ATPase, which can progressively cause respiratory distress syndrome. The virus may infect endothelial cell (EC) which, being less energetic, cannot withstand the huge energy requirement towards viral replication. There - fore glycolysis, the prime energy generating pathway, must be mandatorily upregulated. This can be achieved by Hypoxia-inducible factor-1 (HIF-1). However, HIF-1 also activates transcription of von Willebrand factor, plasminogen activator inhibitor-1, and suppresses the release of thrombomodulin. This in turn sets off the coagulation cascade that can lead to in-situ pulmonary thrombosis and micro clots. The proposed HIF-1 hypothesis justifies various features, biochemical alteration, laboratory as well as autopsy findings such as respiratory distress syndrome, increased blood ferritin and lactate levels, hypoalbuminemia, endothelial invasion, in-situ pulmonary thrombosis and micro clots, and multi-organ failure in COVID-19.

Translated abstract

Istraživači širom sveta iskusili su dualnu prirodu teškog akutnog sindroma koronavirusa-2 (SARS-CoV-2), koji je tragično letalan za neke ljude, a iznenađujuće benigan za druge. Brojne su studije vezano za novo korona virus oboljenje (COVID-19), koji uglavnom oštećuje pluća, ali i ima i iznenađujuće efekte na srce, bubrege i mozak. Istraživači takođe sakupljaju podatke zašto ljudi umiru od COVID-19, bez obzira da li je to samo respiratorni poremećaj, poremećaj koagulacije ili je multi-organski poremećaj. Promene laboratorijskih parametara kako što su laktat, feritin i albumin su ustanovljeni kao faktori rizika, mada još uvek nisu naučno dovoljno potvrđeni. SARS-CoV-2 deluje na alveolarne tip II epitelijelne ćelije koje značajno oštećuju površinsku homeostazu, deluju na Na,K-ATPazu, odnosno vrše oštećenje alveolarne tečnosti koja zatim postepeno umanjuje izmenu alveolarnih gasova i dovodi do izmene intracelularnih hipoksičnih uslova. Ova aktivnosti AMP-aktivirane kinaze, koja zatim inhibira Na,K,ATPazu, što zatim može progresivno da prouzrokuje respiratorni distres sindrom. Virus može da inficira endotelijalne ćelije (E]) koje postaju manje energetske, i nisu sposobne da obezbede dovoljno energetskih potreba prema viralnoj replikaciji. Prema tome, glikoliza, primarni energetski put mora da se u prvom redu reguliše. Ovo može da se postigne sa Hipoksija inducibilnim faktorom-1 (HIF-1). Međutim, HIF-1 takođe aktivira transkripciju von Willebrandovog faktora plazminogen aktivator inhibitora-1, i deluje supresivno na oslobađanje trombomodulina. Ovo nasuprot dovodi do koagulacione kaskade koja može da dovede in-situ pulmolarnu trombozu i mikro koagulaciju. Predložena HIF-1 hipoteza potvrđuje različite događaje, biohemijske promene, laboratorijske nalaze, kao i nalaze autopsije kao što su respiratorni distres sindrom, povećan nivo feritina i laktata u krvi, hipoalbuminemiju, endotelijalnu invaziju, in-situ pulmolarnu trombozu i mikro koagulaciju, kao i oštećenje brojnih organa u COVID-19.