pmedpharmФармация и фармакологияPharmacy & Pharmacology2307-92662413-2241Pyatigorsk Medical and Pharmaceutical Institute - branch of Volgograd State Medical Univer10.19163/2307-9266-2020-8-6-380-391pmedpharm-767Research ArticleОБЗОРЫ, ЛЕКЦИИREVIEWS, LECTURESМЕХАНИЗМЫ РАЗВИТИЯ ЦИТОКИНОВОГО ШТОРМА ПРИ COVID-19 И НОВЫЕ ПОТЕНЦИАЛЬНЫЕ МИШЕНИ ФАРМАКОТЕРАПИИMECHANISMS OF CYTOKINE STORM DEVELOPMENT IN COVID-19 AND NEW POTENTIAL TARGETS OF PHARMACOTHERAPYhttps://orcid.org/0000-0002-0258-4092ПетровВ. И.PetrovV. I.

доктор медицинских наук, профессор, академик РАН, заведующий кафедрой клинической фармакологии и интенсивной терапии ФГБОУ ВО «Волгоградский государственный медицинский университет» Минздрава России; главный внештатный специалист - клинический фармаколог Министерства здравоохранения Российской Федерации, заслуженный деятель науки РФ, заслуженный врач РФ

Doctor of Sciences (Medicine), Professor, Academician of Russian Academy of Sciences, the Head of the Department of Clinical Pharmacology and Intensive Care, Volgograd State Medical University, Chief Freelance Specialist - Clinical Pharmacologist of the Ministry of Health of the Russian Federation, Honored Scientist of the Russian Federation, Honored Physician of the Russian Federation

brain@sprintnet.ruhttps://orcid.org/0000-0003-4539-7577АмосовА. А.AmosovA. A.

студент 6-го курса лечебного факультета ФГБОУ ВО «Волгоградский государственный медицинский университет» Минздрава России

6th year student of the medical faculty of Volgograd State Medical University

aleksandr.amosov.1998@mail.ruhttps://orcid.org/0000-0002-7957-3770ГерасименкоА. С.GerasimenkoA. S.

ассистент кафедры клинической фармакологии и интенсивной терапии ФГБОУ ВО «Волгоградский государственный медицинский университет» Минздрава России

Assistant of Department of Clinical Pharmacology and Intensive Care of Volgograd State Medical University

16any_61@mail.ruhttps://orcid.org/0000-0002-7311-4549ШаталоваО. В.ShatalovaO. V.

доктор медицинских наук, профессор кафедры клинической фармакологии и интенсивной терапии ФГБОУ ВО «Волгоградский государственный медицинский университет» Минздрава России

Doctor of Sciences (Medicine), Professor of the Department of Clinical Pharmacology and Intensive Care of Volgograd State Medical University

shov_med@mail.ruhttps://orcid.org/0000-0002-8237-8335ПономареваА. В.PonomarevaA. V.

доктор медицинских наук, профессор кафедры клинической фармакологии и интенсивной терапии, ФГБОУ ВО «Волгоградский государственный медицинский университет» Минздрава России

Doctor of Sciences (Medicine), Professor of the Department of Clinical Pharmacology and Intensive Care of Volgograd State Medical University

angelvr@yandex.ruhttps://orcid.org/0000-0002-5428-3179АкинчицА. Н.AkinchitsA. N.

доктор медицинских наук, доцент, первый проректор ФГБОУ ВО «Волгоградский государственный медицинский университет» Минздрава России

Doctor of Sciences (Medicine), Associate Professor, First Vice-Rector of Volgograd State Medical University

aakochetova@volgmed.ruhttps://orcid.org/0000-0002-2717-8218КулаковаИ. С.KulakovaI. S.

студентка 6 курса лечебного факультета ФГБОУ ВО «Волгоградский государственный медицинский университет» Минздрава России

6th year student of the medical faculty of Volgograd State Medical University

iraida97@mail.ruhttps://orcid.org/0000-0002-6565-2566ГорбатенкоВ. С.GorbatenkoV. S.

кандидат медицинских наук, доцент кафедры клинической фармакологии и интенсивной терапии ФГБОУ ВО «Волгоградский государственный медицинский университет» Минздрава России

Candidate of Sciences (Medicine), Associate Professor of the Department of Clinical Pharmacology and Intensive Care of Volgograd State Medical University

vlad30.03@mail.ruФедеральное государственное бюджетное образовательное учреждение высшего профессионального образования «Волгоградский государственный медицинский университет» Министерства здравоохранения Российской ФедерацииРоссияVolgograd State Medical UniversityRussian Federation20201705202186380391Copyright © Петров В.И., Амосов А.А., Герасименко А.С., Шаталова О.В., Пономарева А.В., Акинчиц А.Н., Кулакова И.С., Горбатенко В.С., 20212021Петров В.И., Амосов А.А., Герасименко А.С., Шаталова О.В., Пономарева А.В., Акинчиц А.Н., Кулакова И.С., Горбатенко В.С.Petrov V.I., Amosov A.A., Gerasimenko A.S., Shatalova O.V., Ponomareva A.V., Akinchits A.N., Kulakova I.S., Gorbatenko V.S.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pharmpharm.ru/jour/article/view/767

Для тяжёлых форм COVID-19 характерно развитие «цитокинового шторма» – состояния неконтролируемого высвобождения большого количества медиаторов воспаления. Присоединение S-гликопротеина SARS-CoV-2 к ангиотензин-превращающему ферменту 2 рассматривается как процесс, запускающий сложные молекулярные взаимодейтсвия, которые приводят к гипервоспалению, которое в свою очередь реализуется через несколько систем: ренин-ангиотензин-альдостероновую, калликреин-кининовую и систему комплемента. Знание данных механизмов позволяет предположить потенциальные точки терапевтического вмешательства, на которые можно воздействовать существующими терапевтическими средствами для противостояния «цитокиновому шторму» и лечения острого респираторного дистресс-синдрома, связанного с COVID-19.

Цель

Цель. В обзоре обобщаются известные на сегодняшний день данные по молекулярным процессам, лежащим в основе неконтролируемого «цитокинового шторма» у пациентов с тяжёлой формой COVID-19 и возможные варианты их фармакологической коррекции.

Материалы и методы

Материалы и методы. В системах Medline, Cochrane Central Register of Controlled Trials, Scopus, Web of Science Core Collection, Cochrane Library, ClinicalTrials.gov, Elibrary, Google-академия был проведен поиск по ключевым словам и комбинации этих слов: COVID-19, ренин-ангиотензин-альдостероновая система, брадикинин, система комплемента, гиалуроновая кислота, фармакотерапия.

Результаты

Результаты. Развитие «цитокинового шторма» при COVID-19 опосредованно патогенетическими изменениями, происходящими в организме в ответ на проникновения SARS-CoV-2 в клетку. В РААС подавление АПФ2 приводит к снижению его способности расщеплять АТII,

The development of a "cytokine storm", characteristic of severe COVID-19 forms, can be defined as a state of uncontrolled release of a large number of inflammatory mediators.

The attachment of SARS-CoV-2 S-glycoprotein to angiotensin-converting enzyme 2 is considered a process that triggers complex molecular interactions that lead to hyperinflammation. In its turn, it is realized through several systems: renin-angiotensin-aldosterone, kallikrein-kinin and a complement system. Knowledge of these mechanisms suggests potential therapeutic interventions that can be targeted by existing therapeutic agents to counter the cytokine storm and treat the acute respiratory distress syndrome associated with COVID-19.

The aim of the review article is to summarize the currently known data on the molecular processes underlying the uncontrolled "cytokine storm" in the patients with severe COVID-19, and possible options for their pharmacological correction.

Materials and methods

Materials and methods. The data base was represented by such systems as Medline, Cochrane Central Register of Controlled Trials, Scopus, Web of Science Core Collection, Cochrane Library, ClinicalTrials.gov, Elibrary, Google-Academy. A search was carried out for the following keywords and combinations: COVID-19, renin-angiotensin-aldosterone system, bradykinin, complement system, hyaluronic acid, pharmacotherapy.

Results

Results. The development of a "cytokine storm" in COVID-19 is mediated by pathogenetic changes in the body in response to the penetration of SARS-CoV-2 into the cell. In the RAAS, suppression of ACE2 leads to a decrease in its ability to degrade ATII, which, on the one hand, leads to a decrease in the amount of AT1-7, and, on the other hand, to the effect of ATII on AT1R with the subsequent development of vasoconstriction and lung damage. The disturbances in the kallikrein-kinin system are associated, on the one hand, with the increased expression of kallikrein and an increase in the formation of bradykinin and its metabolite des-Arg 9-bradykinin. On the other hand, the disturbances are associated with the suppression of the expression of the C1-esterase inhibitor which prevents the formation of kallikrein, and impaired inactivation of des-Arg 9-bradykinin under the action of ACE 2. The nucleocapsid protein SARS-CoV-2 triggers the activation of the complement system through the lectin pathway. It leads to the production of anaphylatoxins C3a and C5a, which stimulate the synthesis of pro-inflammatory cytokines. Proinflammatory cytokines are potent inducers of the HAS 2 gene in the endothelium, which encodes the membrane enzymes of hyaluronate synthase. The sweating of the fluid into the alveoli caused by the "bradykinin storm" in combination with the overproduction of hyaluronic acid, which accumulates water 1000 times its own mass, can lead to the formation of a dense jelly-like substance that prevents gas exchange.

Conclusion

Conclusion. Promising areas of pharmacotherapy for "cytokine storm" are associated with its impact on the dysfunction of the listed above systems. However, the efficacy and safety of most drugs for the treatment of COVID-19, is to be studied through carefully designed clinical trials.

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The authors declare that there are no conflicts of interest present.