Cellular and molecular mechanisms of COVID-19 pathogenesis, systemic dysregulation and therapy targets


DOI: https://dx.doi.org/10.18565/therapy.2022.10.98-105

Gomazkov O.A.

V.N. Orekhovich Research Institute of Biomedical Chemistry, Moscow
Abstract. Accumulated clinical experience shows that the pathogenesis of respiratory distress syndrome in patients with COVID-19 has a huge range of manifestations. The key component of this pathogenesis is endothelial dysfunction and dysregulation of multiple molecular and cellular control systems for blood coagulation, microhemodynamics, diffusion, hyperinflammation, and immunothrombosis, which is referred to in this review as «storm-2». From the viewpoint of pathophysiology, COVID-19 is a dissonance of a large number of cellular and molecular components, functional details that make up homeostasis, which, under conditions of viral aggression, work as a sequential destruction system. The processes of biochemical and cellular disorganization caused by the SARS-CoV-2 coronavirus reflect the key links in the pathogenesis of a new coronavirus infection. Identification of these links determines the search for effective approaches to the treatment of COVID-19 using both traditional and innovative curative facilities.
Keywords: «storm-2», immunothrombosis, multiple organ complications, «cytokine storm», COVID-19 pandemic, endothelial dysfunction
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Literature

1. da Rosa Mesquita R., Francelino Silva Junior L.C., Santos Santana F.M. et al. Clinical manifestations of COVID-19 in the general population: Systematic review. Wien Klin Wochenschr. 2021; 133(7–8): 377–82. https://dx.doi.org/10.1007/s00508-020-01760-4.


2. Методические рекомендации «Особенности течения Long-COVID-инфекции. Терапевтические и реабилитационные мероприятия». Терапия. 2022; 8(1S): 1–147. [Methodological recommendations «Features of Long-COVID infection clinical course. Therapeutic and rehabilitation measures». Terapiya = Therapy. 2022; 8(1S): 1–147 (In Russ.)]. https://dx.doi.org/10.18565/therapy.2022.1suppl.1-147.


3. Lu R., Zhao X., Li J. et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. Lancet. 2020; 395(10224): 565–74. https://dx.doi.org/10.1016/ S0140-6736(20)30251-8.


4. Tai W., He L., Zhang X. et al. Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: Implication for development of RBD protein as a viral attachment inhibitor and vaccine. Cell Mol Immunol. 2020; 17(6): 613–20. https://dx.doi.org/10.1038/s41423-020-0400-4.


5. Гомазков О.А. Нейропилин – новый игрок в патогенезе COVID-19. Нейрохимия. 2022; 39(2): 124–130. [Gomazkov O.A. Neuropylin is a new player in the pathogenesis of COVID-19. Neyrokhimiya = Neurochemistry. 2022; 39(2): 124–130 (In Russ.)]. https://dx.doi.org/10.31857/S1027813322020066. EDN: MQFFVM.


6. Ye Q., Wang B., Mao J. The pathogenesis and treatment of the «cytokine storm» in COVID-19. J Infect. 2020; 80(6): 607–13. https://dx.doi.org/10.1016/j.jinf.2020.03.037.


7. Гомазков О.А. Эндотелий – эндокринное древо. Природа. 2000; 5: 38–46. [Gomazkov O.A. Endothelium is an endocrine tree. Priroda = Nature. 2000; 5: 38–46 (In Russ.)].


8. Иванов А.Н., Пучиньян Д.М., Норкин И.А. Барьерная функция эндотелия, механизмы ее регуляции и нарушения. Успехи физиологических наук. 2015; 46(2): 72–96. [Ivanov A.N., Puchinyan D.M., Norkin I.A. Vascular endothelial barrier function. Advances in Physiological Sciences. 2015; 46(2): 72–96 (In Russ.)]. EDN: UBFFRL.


9. Путилина М.В. Эндотелий – мишень для новых терапевтических стратегий при сосудистых заболеваниях. Журнал неврологии и психиатрии им. C.C. Корсакова. 2017; 117(10): 122–130. [Putilina M.V. Endothelium as a target for new therapeutic strategies in cerebral vascular diseases. Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova =S.S. Korsakov Journal of Neurology and Psychiatry. 2017; 117(10): 122–130 (In Russ.)]. https://dx.doi.org/10.17116/jnevro2017117101122-130. EDN: ZTSSKJ.


10. Степанова Т.В., Иванов А.Н., Попыхова Э.Б., Лагутина Д.Д. Молекулярные маркеры эндотелиальной дисфункции. Современные проблемы науки и образования. 2019; 1: 37. [Stepanova T.V., Ivanov A.N., Popykhova E.B., Lagutina D.D. Molecular markers of the endothelial dysfunction. Sovremennyye problemy nauki i obrazovaniya = Modern Problems of Science and Education. 2019; 1: 37 (In Russ.)]. EDN: YYHRHN.


11. Sardu C., Gambardella J., Morelli M.B. et al. Hypertension, thrombosis, kidney failure, and diabetes: Is COVID-19 an endothelial disease? A comprehensive evaluation of clinical and basic evidence. J Clin Med. 2020; 9(5): 1417. https://dx.doi.org/10.3390/jcm9051417.


12. Varga Z., Flammer A.J., Steiger P. et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020; 395(10234): 1417–18. https://dx.doi.org/10.1016/S0140-6736(20)30937-5.


13. Marchandot B., Sattler L., Jesel L. et al. COVID-19 related coagulopathy: A distinct entity? J Clin Med. 2020; 9(6): 1651. https://dx.doi.org/10.3390/jcm9061651.


14. Tang N., Li D., Wang X., Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020; 18(4): 844–47. https://dx.doi.org/10.1111/jth.14768.


15. Ciceri F., Luigi Beretta L., Anna Mara Scandroglio A-M. et al. Microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome: An atypical acute respiratory distress syndrome working hypothesis. Crit Care Resusc. 2020; 22(2): 95–97. Online ahead of print.


16. Cure E., Cure M.C. COVID-19 may predispose to trombosis by affecting both vascular endothelium and platelets. Clin Appl Thromb Hemost. 2020; 26: 1076029620933945. https://dx.doi.org/10.1177/1076029620933945.


17. Kangussu L.M., Marzano L.A.S., Souza C.F. et al. The renin-angiotensin system and the cerebrovascular diseases: experimental and clinical evidence. Protein Pept Lett. 2020; 27(6): 463–75. https://dx.doi.org/10.2174/0929866527666191218091823.


18. Mahmudpour M., Roozbeh J., Keshavarz M. et al. COVID-19 cytokine storm: The anger of inflammation. Cytokine. 2020; 133: 155151. https://dx.doi.org/10.1016/j.cyto.2020.155151.


19. Nagele M.P., Haubner B., Tanner F.C. et al. Endothelial dysfunction in COVID-19: Current findings and therapeutic implications. Atherosclerosis. 2020; 314: 58–62. https://dx.doi.org/10.1016/j.atherosclerosis.2020.10.014.


20. Fang C., Schmaier A.H. Novel antithrombotic mechanisms mediated by Mas receptor as result of balanced activities between the kallikrein/kinin and the renin-angiotensin systems. Pharmacol Res. 2020; 160: 105096. https://dx.doi.org/10.1016/j.phrs.2020.105096.


21. van de Veerdonk F.L., Netea M.G., van Deuren M. et al. Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome. Elife. 2020; 9: e57555. https://dx.doi.org/10.7554/eLife.57555.


22. Kreutz R., Algharably E., Ganten D. et al. [Renin-angiotensin-system (RAS) and COVID-19. On the prescription of RAS blockers. Dtsch Med Wochenschr. 2020; 145(10): 682–86 (In German)]. https://dx.doi.org/10.1055/a-1152-3469.


23. Гомазков О.А. COVID-19. Патогенез сосудистых поражений, или дьявол кроется в деталях. М.: ИКАР. 2021; 72 с. [Gomazkov O.A. COVID-19. The pathogenesis of vascular lesions, or the devil is in the details. Moscow: IKAR. 2021; 72 pp. (In Russ.)]. ISBN: 978-5-7974-0730-0.


24. Gomazkov O.A. Damage of the vascular endothelium as a leading mechanism of COVID-19 systemic pathology. Biology Bull Reviews. 2021; 11(6): 559–66. https://dx.doi.org/10.1134/S2079086421060049.


25. Временные методические рекомендации «Профилактика, диагностика и лечение новой коронавирусной инфекции (COVID-19)». Версия 16 (18.08.2022). Минздрав России. Доступ: https://static-0.minzdrav.gov.ru/system/attachments/attaches/000/060/193/original/BMP_COVID-19_V16.pdf (дата обращения – 01.12.2022). [Interim guidelines «Prevention, diagnosis and treatment of novel coronavirus infection (COVID-19)». Version 16 (08/18/2022). Ministry of Healthcare of Russia. URL: https://static-0.minzdrav.gov.ru/system/attachments/attaches/000/060/193/original/BMP_COVID-19_V16.pdf (date of access – 01.12.2022) (In Russ.)].


26. Choudhary S., Sharma K., Silakari O. The interplay between inflammatory pathways and COVID-19: A critical review on pathogenesis and therapeutic options. Microb Pathog. 2021; 150: 104673. https://dx.doi.org/10.1016/j.micpath.2020.104673.


27. O’Sullivan J., Mc Gonagle D., Ward S.E. et al. Endothelial cells orchestrate COVID-19 coagulopathy. Lancet Haematol. 2020; 7(8): e553–e555. https://dx.doi.org/10.1016/S2352-3026(20)30215-5.


28. Fox S.E., Akmatbekov A., Harber J.L. et al. Pulmonary and cardiac pathology in African American patients with COVID-19: An autopsy series. Lancet Respir Med. 2020; 8(7): 681–86. https://dx.doi.org/10.1016/S2213-2600(20)30243-5.


29. Levi M. COVID-19 coagulopathy vs disseminated intravascular coagulation. Blood Adv. 2020; 4(12): 2850. https://dx.doi.org/10.1182/bloodadvances.2020002197.


30. Engelmann B., Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol. 2013; 13(1): 34–45. https://dx.doi.org/10.1038/nri3345.


31. Jayarangaiah A., Kariyanna P.T., Chen X. et al. COVID-19-associated coagulopathy: An exacerbated immunothrombosis response. Clin Appl Thromb Hemost. 2020; 26: 1076029620943293. https://dx.doi.org/10.1177/1076029620943293.


32. Leppkes M., Knopf J., Naschberger E. et al. Vascular occlusion by neutrophil extracellular traps in COVID-19. EBioMedicine. 2020; 58: 102925. https://dx.doi.org/10.1016/j.ebiom.2020.102925.


33. Бицадзе В.О., Слуханчук Е.В., Хизроева Д.Х. с соавт. Внеклеточные ловушки нейтрофилов (NETs) в патогенезе тромбоза и тромбовоспалительных заболеваний. Вестник Российской академии медицинских наук. 2021; 76(1): 75–85. [Bitsadze V.O., Slukhanchuk E.V., Khizroeva J.H. et al. Extracellular neutrophil traps (NETS) in the pathogenesis of thrombosis and thromboinflammation. Vestnik Rossiyskoy akademii meditsinskikh nauk = Herald of the Russian Academy of Medical Sciences. 2021; 76(1): 75–85 (In Russ.)]. https://dx.doi.org/10.15690/vramn1395. EDN: YOYFZY.


34. Кассина Д.В., Василенко И.А., Гурьев А.С. с соавт. Нейтрофильные внеклеточные ловушки: значение для диагностики и прогноза COVID-19. Альманах клинической медицины. 2020; 48(S1): 43–50. [Kassina D.V., Vasilenko I.A., Guriev A.S. et al. Neutrophil extracellular traps: diagnostic and prognostic value in COVID-19. Al’manakh klinicheskoy meditsiny = Almanac of Clinical Medicine. 2020; 48(S1): 43–50 (In Russ.)]. https://dx.doi.org/10.18786/2072-0505-2020-48-029. EDN: UOHMXR.


35. Han F., Liu Y., Mo M. et al. Current treatment strategies for COVID‑19 (Review). Mol Med Rep. 2021; 24(6): 858. https://dx.doi.org/10.3892/mmr.2021.12498.


36. Niknam Z., Jafari A., Golchin A. et al. Potential therapeutic options for COVID-19: An update on current evidence. Eur J Med Res. 2022; 27(1): 6. https://dx.doi.org/10.1186/s40001-021-00626-3.


37. Первый медицинский канал. «Репозиционирование лекарств». Гость: Поройков В.В. Доступ: https://www.youtube.com/watch?v=O9BHh1tp1pI (дата обращения – 01.12.2022). [First Medical Channel. «Drug repositioning». Guest: Poroikov V.V. URL: https://www.youtube.com/watch?v=O9BHh1tp1pI (date of access – 01.12.2022) (In Russ.)].


38. Савосина П.И., Дружиловский Д.С., Поройков В.В. COVID-19: анализ практики репозиционирования лекарственных препаратов. Химико-фармацевтический журнал. 2020; 54(10): 7–14. [Savosina P.I., Druzhilovskii D.S., Poroikov V.V. COVID-19: analysis of drug repositioning practice. Khimiko-farmatsevticheskiy zhurnal = Chemical Pharmaceutical Journal. 2020; 54(10): 7–14 (In Russ.)]. https://dx.doi.org/10.30906/0023-1134-2020-54-10-7-14. EDN: MFKKKM.


About the Autors

Oleg A. Gomazkov, Doctor of biological sciences, professor, chief researcher at V.N. Orekhovich Research Institute of Biomedical Chemistry. Address: 119121, Moscow, 10/8 Pogodinskaya Str. E-mail: oleg-gomazkov@yandex.ru. ORCID: http://orcid.org/0000-0002-4600-4424


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