Some Aspects of Mast Cells Carboxypeptidase A3 Participation in the Pathogenesis of COVID-19

ORIGINAL ARTICLE
Andrey V. Budnevsky, Sergey N. Avdeev, Evgeniy S. Ovsyannikov, Nadezhda G. Alekseeva, Victoria V. Shishkina, Inessa A. Savushkina, Inna M. Perveeva, Sofia N. Feigelman, Avag G. Kitoyan, Valeria R. Drobysheva

 
International Journal of Biomedicine. 2023;13(4):301-305.
DOI: 10.21103/Article13(4)_OA11
Originally published December 5, 2023

Abstract: 

Background: This study aimed to determine the involvement of carboxypeptidase A3 (CPA3) in developing lung damage in patients with COVID-19.
Methods and Results: The study included samples of autopsy material from the lungs of patients who died as a result of severe COVID-19 (the main group [MG] and persons who died from external causes (the control group [CG]). Immunohistochemical staining for CPA3 was carried out. A quantitative study of CPA3-positive mast cells (MCs) and the degree of their degranulation was carried out using a ×40 objective lens with an analysis of ≥50 fields of view with further conversion to 1 mm².
Significant representation of CPA3-positive MCs per 1 mm2 of CPA3-positive MCs, CPA3-positive MCs with signs of degranulation (SD), and co-adjacent MCs was found in the MG compared to the CG (P=0.01 in all cases). In the main group, positive correlations were identified between the total number of CPA3-positive MCs, CPA3-positive MCs with SD and the blood hemoglobin level shortly before death (r=0.491 [P=0.008] and r=0.521 [P=0.004], respectively). Co-adjacent CPA3-positive MCs were negatively correlated with blood eosinophils at the beginning of hospitalization (r=-0.420 [P=0.023]). Also, the number of separately lying, CPA3-positive MCs negatively correlated with the blood monocyte shortly before death (r=-0.384 [P=0.044]). A positive correlation was established between the total number of CPA3-positive MCs, CPA3-positive MCs with SD, and adjacent CPA3-positive MCs with total blood protein in patients at the beginning of hospitalization (r=0.431 [P=0.020], r=0.449 [P=0.015] and r=0.456 [P=0.013], respectively). In addition, the study demonstrated a positive correlation between CPA3-positive MCs with SD and the total number of CPA3-positive MCs with blood aPTT levels (r=0.304 [P=0.045] and r=0.375 [P=0.045], respectively). A negative correlation was also found between the total number of CPA3-positive MCs and the blood INR level (r=-0.812 [P=0.050]). Finally, in patients at the beginning of hospitalization, a negative correlation was found between CPA3-positive MCs with SD, CPA3-positive MCs without SD, separately located CPA3-positive MCs, adjacent CPA3-positive MCs, and the total number of CPA3-positive MCs with blood amylase (r=-0.550 [P=0.002], r=-0.452 [P=0.045], r=-0.485 [P=0.030], r=-0.622 [P=0.008], and r=-0.590 [P=0.006], respectively).
Conclusion: Our study identifies the potential involvement of CPA3 in the pathogenesis of severe COVID-19. However, many aspects of its participation remain unclear and require further study.

References: 
  1. Sohrabi C, Alsafi Z, O'Neill N, Khan M, Kerwan A, Al-Jabir A, Iosifidis C, Agha R. World Health Organization declares global emergency: A review of the 2019 novel coronavirus (COVID-19). Int J Surg. 2020 Apr;76:71-76. doi: 10.1016/j.ijsu.2020.02.034. Epub 2020 Feb 26. Erratum in: Int J Surg. 2020 May;77:217. PMID: 32112977; PMCID: PMC7105032.
  2. Azkur AK, Akdis M, Azkur D, Sokolowska M, van de Veen W, Brüggen MC, O'Mahony L, Gao Y, Nadeau K, Akdis CA. Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19. Allergy. 2020 Jul;75(7):1564-1581. doi: 10.1111/all.14364. PMID: 32396996; PMCID: PMC7272948.
  3. Kritas SK, Ronconi G, Caraffa A, Gallenga CE, Ross R, Conti P. Mast cells contribute to coronavirus-induced inflammation: new anti-inflammatory strategy. J Biol Regul Homeost Agents. 2020 January-February,;34(1):9-14. doi: 10.23812/20-Editorial-Kritas. PMID: 32013309.
  4. Kempuraj D, Selvakumar GP, Ahmed ME, Raikwar SP, Thangavel R, Khan A, Zaheer SA, Iyer SS, Burton C, James D, Zaheer A. COVID-19, Mast Cells, Cytokine Storm, Psychological Stress, and Neuroinflammation. Neuroscientist. 2020 Oct-Dec;26(5-6):402-414. doi: 10.1177/1073858420941476. Epub 2020 Jul 18. PMID: 32684080.
  5. Ovsyannikov ES, Avdeev SN, Budnevsky AV, Drobysheva ES, Kravchenko AYa. COVID-19 and chronic obstructive pulmonary disease: the known about the unknown. Tuberculosis and lung diseases. 2021; 99(2):6-15.
  6. Buchwalow IB, Böcker W. Immunohistochemistry: basics and methods. – Springer Science & Business Media, 2010.
  7. Siddhuraj P, Clausson CM, Sanden C, Alyamani M, Kadivar M, Marsal J, Wallengren J, Bjermer L, Erjefält JS. Lung Mast Cells Have a High Constitutive Expression of Carboxypeptidase A3 mRNA That Is Independent from Granule-Stored CPA3. Cells. 2021 Feb 3;10(2):309. doi: 10.3390/cells10020309. PMID: 33546258; PMCID: PMC7913381.
  8. Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, et al.  Proteomics. Tissue-based map of the human proteome. Science. 2015 Jan 23;347(6220):1260419. doi: 10.1126/science.1260419. PMID: 25613900.
  9. Yaroshetsky AI, Gritsan AI, Avdeev SN, Vlasenko AV, Eremenko AA, Zabolotskikh IB, et al. Diagnostics and intensive therapy of Acute Respiratory Distress Syndrome (Clinical guidelines of the Federation of Anesthesiologists and Reanimatologists of Russia). Russian Journal of Anesthesiology and Reanimatology. 2020;(2):5‑39. (In Russ.) doi :10.17116/anaesthesiology20200215
  10. Buchwalow I. B., Böcker W. Immunohistochemistry: basics and methods. – Springer Science & Business Media, 2010.
  11. Budnevsky AV, Avdeev SN, Ovsyannikov ES, Shishkina VV, Esaulenko DI, Filin АА, et al. The role of mast cells and their proteases in lung damage associated with COVID-19. Pulmonologia. 2023; 33(1):17-26.
  12. Jafarzadeh A, Chauhan P, Saha B, Jafarzadeh S, Nemati M. Contribution of monocytes and macrophages to the local tissue inflammation and cytokine storm in COVID-19: Lessons from SARS and MERS, and potential therapeutic interventions. Life Sci. 2020 Sep 15;257:118102. doi: 10.1016/j.lfs.2020.118102. Epub 2020 Jul 18. PMID: 32687918; PMCID: PMC7367812.
  13. Budnevsky AV, Ovsyannikov ES, Shishkina VV, Esaulenko DI, Shumilovich BR, Savushkina IA, Alekseeva NG. Possible Unexplored Aspects of COVID-19 Pathogenesis: The Role of Carboxypeptidase A3. International Journal of Biomedicine. 2022; 12(2):179-182.
  14. Abonia JP, Blanchard C, Butz BB, Rainey HF, Collins MH, Stringer K, Putnam PE, Rothenberg ME. Involvement of mast cells in eosinophilic esophagitis. J Allergy Clin Immunol. 2010 Jul;126(1):140-9. doi: 10.1016/j.jaci.2010.04.009. Epub 2010 Jun 9. PMID: 20538331; PMCID: PMC2902643.
  15. Dougherty RH, Sidhu SS, Raman K, Solon M, Solberg OD, Caughey GH, Woodruff PG, Fahy JV. Accumulation of intraepithelial mast cells with a unique protease phenotype in T(H)2-high asthma. J Allergy Clin Immunol. 2010 May;125(5):1046-1053.e8. doi: 10.1016/j.jaci.2010.03.003. PMID: 20451039; PMCID: PMC2918406.
  16. Palladino M. Complete blood count alterations in COVID-19 patients: A narrative review. Biochem Med (Zagreb). 2021 Oct 15;31(3):030501. doi: 10.11613/BM.2021.030501. PMID: 34658642; PMCID: PMC8495616.
  17. Dubey L, Dorosh O, Dubey N, Doan S, Kozishkurt O, Duzenko O, Kozlova O, Ievtukh V, Ladny JR, Pruc M, Szarpak L, Pukach J. COVID-19-induced coagulopathy: Experience, achievements, prospects. Cardiol J. 2023;30(3):453-461. doi: 10.5603/CJ.a2022.0123. Epub 2023 Jan 2. PMID: 36588310; PMCID: PMC10287077.
  18. Jin X, Duan Y, Bao T, Gu J, Chen Y, Li Y, Mao S, Chen Y, Xie W. The values of coagulation function in COVID-19 patients. PLoS One. 2020 Oct 29;15(10):e0241329. doi: 10.1371/journal.pone.0241329. PMID: 33119703; PMCID: PMC7595402.
  19. Siddhuraj P, Jönsson J, Alyamani M, Prabhala P, Magnusson M, Lindstedt S, Erjefält JS. Dynamically upregulated mast cell CPA3 patterns in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Front Immunol. 2022 Aug 2;13:924244. doi: 10.3389/fimmu.2022.924244. PMID: 35983043; PMCID: PMC9378779.
  20. Abramczyk U, Nowaczyński M, Słomczyński A, Wojnicz P, Zatyka P, Kuzan A. Consequences of COVID-19 for the Pancreas. Int J Mol Sci. 2022 Jan 13;23(2):864. doi: 10.3390/ijms23020864. PMID: 35055050; PMCID: PMC8776154.

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Received October 17, 2023.
Accepted November 25, 2023.
©2023 International Medical Research and Development Corporation.