ISSN 2412-4036 (print)
ISSN 2713-1823 (online)

Comparative assessment of protease activity of mast cells in heart and pulmonary tissues in case of COVID-19

Budnevsky A.V., Avdeev S.N., Arkhipova E.D., Shishkina V.V., Chernik T.A., Filin A.A.

1) N.N. Burdenko Voronezh State Medical University of the Ministry of Healthcare of Russia; 2) I.M. Sechenov First Moscow State Medical University of the Ministry of Healthcare of Russia (Sechenov University)
Abstract. Some data on the contribution of mast cells (MC) to lung damage in case of COVID-19 are existing. However, information on cardiac MC in the new coronavirus infection is limited and contradictory. These factors generate interest in studying the contribution of MCs to cardiac injury in case of new coronavirus infection.
The aim: to make a comparative assessment of the protease activity of MCs in pulmonary and cardiac tissues of patients who died due to COVID-19.
Material and methods. The sample consisted of 40 patients (21 male, 19 female, mean age 66.65 ± 7.40 years) hospitalized with a diagnosis of severe and extremely severe COVID-19 and died due to diffuse alveolar damage. Autopsy material of heart and lung tissues was stained with hematoxylin and eosin and by Picro – Mallory staining, as well as immunohistochemical analysis was made. Total number of MCs was counted with distribution by the degree of degranulation, as well as a quantitative analysis of the protease profile (tryptase, chymase, carboxypeptidase A3 (CPA3) per 1 mm2 was made.
Results. The greatest differences in the comparison of MCs protease profile in heart and lung tissues were observed in the number of tryptase-positive MCs: the medians were 2.39 [1.795; 3.42] per 1 mm2 and 23.87 [14.8; 34.53] per 1 mm2, respectively (p = 0.0000). Significant differences remained for all MC phenotypes with their predominance in pulmonary tissues (p = 0.0000). Positive correlations were fixed between the number of MCs in the tissues of studied organs with the highest correlation coefficients for degranulated tryptase-positive MCs (r = 0.4711; p = 0.0001) and the total amount of CPA3-positive MCs (r = 0.5056; p = 0.0319).
Conclusion. MCs of all phenotypes were predominant in the lungs. In both organs (heart and lungs), the largest amount of MCs was represented by tryptase-positive, and the smallest number – by chymase-positive cells. The presence of correlations between MCs in heart and lungs may indicate the involvement of the heart in systemic inflammatory process in case of COVID-19 in all patients, regardless of the presence of clinical manifestations of this organ’s damage.

Keywords

mast cell protease activity
COVID-19
comparative analysis
cardiac mast cells
pulmonary mast cells

References

1. Srinivasan A., Wong F., Couch L.S., Wang B.X. Cardiac complications of COVID-19 in low-risk patients. Viruses. 2022;14(6): 1322.

https://doi.org/10.3390/v14061322. PMID: 35746793. PMCID: PMC9228093.

2. Monkemuller K., Fry L., Rickes S. COVID-19, coronavirus, SARS-CoV-2 and the small bowel. Rev Esp Enferm Dig. 2020; 112(5): 383–88.

https://doi.org/10.17235/reed.2020.7137/2020. PMID: 32343593.

3. Singh L., Kumar A., Rai M. et al. Spectrum of COVID-19 induced liver injury: A review report. World J Hepatol. 2024; 16(4): 517–36.

https://doi.org/10.4254/wjh.v16.i4.517. PMID: 38689748. PMCID: PMC11056898.

4. Кравченко А.Я., Концевая А.В., Будневский А.В., Черник Т.А. Новая коронавирусная инфекция (COVID-19) и патология почек. Профилактическая медицина. 2022; 25(3): 92–97. (Kravchenko A.Ya., Kontsevaya A.V., Budnevsky A.V., Chernik T.A. Novel coronavirus infection (COVID-19) and kidney disease. Profilakticheskaya meditsina = The Russian Journal of Preventive Medicine. 2022; 25(3): 92–97 (In Russ.)).

https://doi.org/10.17116/profmed20222503192. EDN: BUMCKR.

5. Pennisi M., Lanza G., Falzone L. et al. SARS-CoV-2 and the nervous system: From clinical features to molecular mechanisms. Int J Mol Sci. 2020; 21(15): 5475.

https://doi.org/10.3390/ijms21155475. PMID: 32751841. PMCID: PMC7432482.

6. Danarti R., Limantara N.V., Rini D.L.U. et al. Cutaneous manifestation in COVID-19: A lesson over 2 years into the pandemic. Clin Med Res. 2023; 21(1): 36–45.

https://doi.org/10.3121/cmr.2023.1598. PMID: 37130789. PMCID: PMC10153677.

7. Menter T., Haslbauer J.D., Nienhold R. et al. Postmortem examination of COVID-19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings in lungs and other organs suggesting vascular dysfunction. Histopathology. 2020; 77(2): 198–209.

https://doi.org/10.1111/his.14134. PMID: 32364264. PMCID: PMC7496150.

8. Самсонова М.В., Михалева Л.М., Зайратьянц О.В. с соавт. Патология легких при COVID-19 в Москве. Архив патологии. 2020; 82(4): 32–40. (Samsonova M.V., Mikhaleva L.M., Zairatyants O.V. et al. Lung pathology of COVID-19 in Moscow. Archive of Pathology = Arkhiv patologii. 2020; 82(4): 32–40. (In Russ.)).

https://doi.org/10.17116/patol20208204132. EDN: KRPHRJ.

9. Викулова О.К., Зураева З.Т., Никанкина Л.В., Шестакова М.В. Роль ренин-ангиотензиновой системы и ангиотензинпревращающего фермента 2 типа в развитии и течении вирусной инфекции СОVID-19 у пациентов с сахарным диабетом. Сахарный диабет. 2020; 23(3): 242–249. (Vikulova O.K., Zuraeva Z.T., Nikankina L.V., Shestakova M.V. The role of renin-angiotensin system and angiotensin-converting enzyme 2 (ACE2) in the development and course of viral infection COVID-19 in patients with diabetes mellitus. Saharnyj diabet = Diabetes Mellitus. 2020; 23(3): 242–249 (In Russ.)).

https://doi.org/10.14341/dm12501. EDN: HVDENZ.

10. Fu L., Liu X., Su Y. et al. Prevalence and impact of cardiac injury on COVID-19: A systematic review and meta-analysis. Clin Cardiol. 2021; 44(2): 276–283.

https://doi.org/10.1002/clc.23540. PMID: 33382482. PMCID: PMC7852167.

11. Rathore S.S., Rojas G.A., Sondhi M. et al. Myocarditis associated with Covid-19 disease: A systematic review of published case reports and case series. Int J Clin Pract. 2021; 75(11): e14470.

https://doi.org/10.1111/ijcp.14470. PMID: 34235815.

12. Priya S.P., Sunil P.M., Varma S. et al. Direct, indirect, post-infection damages induced by coronavirus in the human body: An overview. Virusdisease. 2022; 33(4): 429–44.

https://doi.org/10.1007/s13337-022-00793-9. PMID: 36311173. PMCID: PMC9593972.

13. Tavazzi G., Pellegrini C., Maurelli M. et al. Myocardial localization of coronavirus in COVID-19 cardiogenic shock. Eur J Heart Fail. 2020; 22(5): 911–15.

https://doi.org/10.1002/ejhf.1828. PMID: 32275347. PMCID: PMC7262276.

14. Varga Z., Flammer A.J., Steiger P. et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020; 395(10234): 1417–18.

https://doi.org/10.1016/S0140-6736(20)30937-5. PMID: 32325026. PMCID: PMC7172722.

15. Будневский А.В., Авдеев С.Н., Овсянников Е.С. с соавт. Роль тучных клеток и их протеаз в поражении легких у пациентов с COVID-19. Пульмонология. 2023; 33(1): 17–26. (Budnevsky A.V., Avdeev S.N., Ovsyannikov E.S. et al. The role of mast cells and their proteases in lung damage associated with COVID-19. Pulmonologiya = Pulmonology. 2023; 33(1): 17–26 (In Russ.)).

https://doi.org/10.18093/0869-0189-2023-33-1-17-26. EDN: KJVTRV.

16. Cao J.-B., Zhu S.-T., Huang X.-S. et al. Mast cell degranulation-triggered by SARS-CoV-2 induces tracheal-bronchial epithelial inflammation and injury. Virol Sin. 2024; 39(2): 309–18.

https://10.1016/j.virs.2024.03.001. PMID: 38458399. PMCID: PMC11074640.

17. Hartmann C., Miggiolaro A.F.R.D.S., Motta J.S. et al. The pathogenesis of COVID-19 myocardial injury: An immunohistochemical study of postmortem biopsies. Front Immunol. 2021; 12: 748417.

https://10.3389/fimmu.2021.748417. PMID: 34804033. PMCID: PMC8602833.

18. Zhou F., Yu T., Du R. et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet. 2020; 395(10229): 1054–62.

https://doi.org/10.1016/S0140-6736(20)30566-3. PMID: 32171076. PMCID: PMC7270627.

19. Lippi G., Lavie C.J., Sanchis-Gomar F. Cardiac troponin I in patients with coronavirus disease 2019 (COVID-19): Evidence from a meta-analysis. Prog Cardiovasc Dis. 2020; 63(3): 390–91.

https://10.1016/j.pcad.2020.03.001. PMID: 32169400. PMCID: PMC7127395.

20. Xanthopoulos A., Bourazana A., Giamouzis G. et al. COVID-19 and the heart. World J Clin Cases. 2022; 10(28): 9970–84.

https://10.12998/wjcc.v10.i28.9970. PMID: 36246800. PMCID: PMC9561576.

21. Zuin M., Rigatelli G., Bilato C. et al. One-year risk of myocarditis after COVID-19 infection: A systematic review and meta-analysis. Can J Cardiol. 2023; 39(6): 839–44.

https://10.1016/j.cjca.2022.12.003. PMID: 36521730. PMCID: PMC9743686.

22. Fremont-Smith M., Gherlone N., Smith N. et al. Models for COVID-19 early cardiac pathology following SARS-CoV-2 infection. Int J Infect Dis. 2021; 113: 331–35.

https://10.1016/j.ijid.2021.09.052. PMID: 34592443. PMCID: PMC8473263.

23. Арташян О.С., Храмцова Ю.С., Тюменцева Н.В. с соавт. Тучные клетки миокарда и адаптация сердца к физической нагрузке. Человек. Спорт. Медицина. 2021; 21(2): 34–41. (Artashyan O.S., Khramtsova Yu.S., Tуumentseva N.V. et al. Cardiac mast cells and adaptation of the heart to physical activity. Chelovek. Sport. Meditsina = Human. Sport. Medicine. 2021; 21(2): 34–41 (In Russ.)).

https://doi.org/10.14529/hsm210204. EDN: UGUJAG.

24. (Li H., Huang L.-F., Wen C. et al. Roles of cardiac mast cells and Toll-like receptor 4 in viral myocarditis among mice. Zhongguo Dang Dai Er Ke Za Zhi. 2013; 15(10): 896–902 (In Chinese)). PMID: 24131845.

25. Fairweather D., Beetler D.J., Di Florio D.N. et al. COVID-19, myocarditis and pericarditis. Circ Res. 2023; 132(10): 1302–19.

https://doi.org/10.1161/circresaha.123.321878. PMID: 37167363. PMCID: PMC10171304.

26. Nappi F., Singh S.S.A. SARS-CoV-2-induced myocarditis: A state-of-the-art review. Viruses. 2023; 15(4): 916.

https://doi.org/10.3390/v15040916. PMID: 37112896. PMCID: PMC10145666.

27. Krysko O., Bourne J.H., Kondakova E. et al. Severity of SARS-CoV-2 infection is associated with high numbers of alveolar mast cells and their degranulation. Front Immunol. 2022; 13: 968981.

https://doi.org/10.3389/fimmu.2022.968981. PMID: 36225927. PMCID: PMC9548604.

28. Атякшин Д.А., Бухвалов И.Б., Тиманн М. Протеазы тучных клеток в формировании специфического тканевого микроокружения: патогенетические и диагностические аспекты. Терапия. 2018; (6): 128–140. (Atyakshin D.A., Bukhvalov I.B., Timann M. Mast cell proteases in specific tissular microenvironment formation: Pathogenetic and diagnostical aspects. Terapiya = Therapy. 2018; (6): 128–140 (In Russ.)).

https://dx.doi.org/10.18565/therapy.2018.6.128-140. EDN: YNNGYH.

29. Wu L., Baylan U., van der Leeden B. et al. Cardiac inflammation and microvascular procoagulant changes are decreased in second wave compared to first wave deceased COVID-19 patients. Int J Cardiol. 2022; 349: 157–65.

https://doi.org/10.1016/j.ijcard.2021.11.079. PMID: 34871622. PMCID: PMC8641429.

About the Authors

Andrey V. Budnevsky, MD, Dr. Sci. (Medicine), professor, head of the Department of faculty therapy, N.N. Burdenko Voronezh State Medical University of the Ministry of Healthcare of Russia. Address: 394036, Voronezh, 10 Studentcheskaya St.
E-mail: avbudnevski@vrngmu.ru
ORCID: https://orcid.org/0000-0002-1171-2746
Sergey N. Avdeev, MD, Dr. Sci. (Medicine), professor, academician of RAS, head of the Department of pulmonology of N.V. Sklifosovsky Institute of Clinical Medicine, I.M. Sechenov First Moscow State Medical University of the Ministry of Healthcare of Russia (Sechenov University). Address: 119048, Moscow, 8/2 Trubetskaya St.
E-mail: serg_avdeev@list.ru
ORCID: https://orcid.org/0000-0002-5999-2150
Ekaterina D. Arkhipova, MD, postgraduate student of the Department of faculty therapy, N.N. Burdenko Voronezh State Medical University of the Ministry of Healthcare of Russia. Address: 394036, Voronezh, 10 Studencheskaya St.
E-mail: e.pavlyukevich@bk.ru
ORCID: https://orcid.org/0009-0002-4960-334X
Victoria V. Shishkina, MD, PhD (Medicine), head of the Department of histology, N.N. Burdenko Voronezh State Medical University of the Ministry of Healthcare of Russia. Address: 394036, Voronezh, 10 Studencheskaya St.
E-mail: v.v.4128069@yandex.ru
ORCID: https://orcid.org/0000-0001-9185-4578
Tatiana A. Chernik, MD, PhD (Medicine), associate professor of the Department of faculty therapy, N.N. Burdenko Voronezh State Medical University of the Ministry of Healthcare of Russia. Address: 394036, Voronezh, 10 Studencheskaya St.
E-mail: ch01@mail.ru
ORCID: https://orcid.org/0000-0003-1371-0848
Andrey A. Filin, MD, PhD (Medicine), head of the Department of pathological anatomy, senior researcher at the Research Institute of Experimental Biology and Medicine, N.N. Burdenko Voronezh State Medical University of the Ministry of Healthcare of Russia. Address: 394036, Voronezh, 10 Studencheskaya St.
E-mail: filinan@yandex.ru
ORCID: https://orcid.org/0000-0003-1670-3694

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