{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T16:55:14Z","timestamp":1778172914408,"version":"3.51.4"},"reference-count":29,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,4,19]],"date-time":"2024-04-19T00:00:00Z","timestamp":1713484800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Recent studies suggested the potential role of mast cells (MCs) in the pathology of coronavirus disease 2019 (COVID-19). However, the precise description of the MCs\u2019 activation and the engagement of their proteases is still missing. The objective of this study was to further reveal the importance of MCs and their proteases (chymase, tryptase, and carboxypeptidase A3 (CPA3)) in the development of lung damage in patients with COVID-19. This study included 55 patients who died from COVID-19 and 30 controls who died from external causes. A histological analysis of the lung parenchyma was carried out to assess the protease profiles and degranulation activity of MCs. In addition, we have analyzed the general blood test, coagulogram, and C-reactive protein. The content of tryptase-positive MCs (Try-MCs) in the lungs of patients with COVID-19 was higher than in controls, but their degranulation activity was lower. The indicators of chymase-positive MCs (Chy-MCs) were significantly lower than in the controls, while the content of CPA3-positive MCs (CPA3-MCs) and their degranulation activity were higher in patients with COVID-19. In addition, we have demonstrated the existence of correlations (positive\/negative) between the content of Try-MCs, Chy-MCs, and CPA3-MCs at different states of their degranulation and presence (co-adjacent\/single) and the levels of various immune cells (neutrophils, eosinophils, basophils, and monocytes) and other important markers (blood hemoglobin, activated partial thromboplastin time (aPTT), international normalized ratio (INR), and fibrinogen). Thus, the identified patterns suggest the numerous and diverse mechanisms of the participation of MCs and their proteases in the pathogenesis of COVID-19, and their impact on the inflammatory process and coagulation status. At the same time, the issue requires further study in larger cohorts of patients, which will open up the possibility of using drugs acting on this link of pathogenesis to treat lung damage in patients with COVID-19.<\/jats:p>","DOI":"10.3390\/cells13080711","type":"journal-article","created":{"date-parts":[[2024,4,19]],"date-time":"2024-04-19T06:28:09Z","timestamp":1713508089000},"page":"711","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Involvement of Mast Cells in the Pathology of COVID-19: Clinical and Laboratory Parallels"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1171-2746","authenticated-orcid":false,"given":"Andrey V.","family":"Budnevsky","sequence":"first","affiliation":[{"name":"Department of Faculty Therapy, Voronezh State Medical University Named after N.N. Burdenko, Studencheskaya Street 10, 394622 Voronezh, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5999-2150","authenticated-orcid":false,"given":"Sergey N.","family":"Avdeev","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Trubetskaya Street 8, 119991 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Djuro","family":"Kosanovic","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Trubetskaya Street 8, 119991 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8545-6255","authenticated-orcid":false,"given":"Evgeniy S.","family":"Ovsyannikov","sequence":"additional","affiliation":[{"name":"Department of Faculty Therapy, Voronezh State Medical University Named after N.N. Burdenko, Studencheskaya Street 10, 394622 Voronezh, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6988-1369","authenticated-orcid":false,"given":"Inessa A.","family":"Savushkina","sequence":"additional","affiliation":[{"name":"Department of Faculty Therapy, Voronezh State Medical University Named after N.N. Burdenko, Studencheskaya Street 10, 394622 Voronezh, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadezhda G.","family":"Alekseeva","sequence":"additional","affiliation":[{"name":"Department of Faculty Therapy, Voronezh State Medical University Named after N.N. Burdenko, Studencheskaya Street 10, 394622 Voronezh, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4128-6044","authenticated-orcid":false,"given":"Sofia N.","family":"Feigelman","sequence":"additional","affiliation":[{"name":"Department of Faculty Therapy, Voronezh State Medical University Named after N.N. Burdenko, Studencheskaya Street 10, 394622 Voronezh, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9185-4578","authenticated-orcid":false,"given":"Viktoria V.","family":"Shishkina","sequence":"additional","affiliation":[{"name":"Department of Faculty Therapy, Voronezh State Medical University Named after N.N. Burdenko, Studencheskaya Street 10, 394622 Voronezh, Russia"},{"name":"Research Institute of Experimental Biology and Medicine, Voronezh State Medical University Named after N.N. Burdenko, Moskovskiy Avenue, 185, 394066 Voronezh, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1670-3694","authenticated-orcid":false,"given":"Andrey A.","family":"Filin","sequence":"additional","affiliation":[{"name":"Department of Faculty Therapy, Voronezh State Medical University Named after N.N. Burdenko, Studencheskaya Street 10, 394622 Voronezh, Russia"},{"name":"Research Institute of Experimental Biology and Medicine, Voronezh State Medical University Named after N.N. Burdenko, Moskovskiy Avenue, 185, 394066 Voronezh, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dmitry I.","family":"Esaulenko","sequence":"additional","affiliation":[{"name":"Research Institute of Experimental Biology and Medicine, Voronezh State Medical University Named after N.N. Burdenko, Moskovskiy Avenue, 185, 394066 Voronezh, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Inna M.","family":"Perveeva","sequence":"additional","affiliation":[{"name":"Voronezh Regional Clinical Hospital No. 1, Moskovskiy Avenue, 151, 394066 Voronezh, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,19]]},"reference":[{"key":"ref_1","unstructured":"(2023, November 02). WHO Coronavirus (COVID-19) Dashboard. Available online: https:\/\/covid19.who.int\/#:~:text=Globally%2C%20as%20of%205%3A57pm%20CEST%2C,6%2C974%2C473%20deaths%2C%20reported%20to%20WHO."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Zanza, C., Romenskaya, T., Manetti, A.C., Franceschi, F., La Russa, R., Bertozzi, G., Maiese, A., Savioli, G., Volonnino, G., and Longhitano, Y. (2022). Cytokine Storm in COVID-19: Immunopathogenesis and Therapy. Medicina, 58.","DOI":"10.3390\/medicina58020144"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1186\/s12967-022-03767-z","article-title":"Innate immunity, cytokine storm, and inflammatory cell death in COVID-19","volume":"20","author":"Karki","year":"2022","journal-title":"J. Transl. Med."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Brock, I., and Maitland, A. (2021). Mast Cells and COVID-19: A case report implicating a role of mast cell activation in the prevention and treatment of COVID-19. J. Vaccines Vaccin., 36\u201339.","DOI":"10.21203\/rs.3.rs-330667\/v1"},{"key":"ref_5","first-page":"175","article-title":"Cytokine storm. Causes and consequences","volume":"42","author":"Potapnev","year":"2021","journal-title":"Immunol.-Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1186\/s12931-022-02284-3","article-title":"Role of mast cells in the pathogenesis of severe lung damage in COVID-19 patients","volume":"23","author":"Budnevsky","year":"2022","journal-title":"Respir. Res"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"128","DOI":"10.18565\/therapy.2018.6.128-140","article-title":"Mast cell proteases in specific tissular microenvironment formation: Pathogenetic and diagnostical aspects","volume":"6","author":"Atyakshin","year":"2018","journal-title":"Therapiya-Therapy"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Sutanto, H. (2024). Mechanobiology of Type 1 hypersensitivity: Elucidating the impacts of mechanical forces in allergic reactions. Mechanobiol. Med., 2.","DOI":"10.22541\/au.170863914.41137652\/v1"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1002\/biof.1633","article-title":"COVID-19, pulmonary mast cells, cytokine storms, and beneficial actions of luteolin","volume":"46","author":"Theoharides","year":"2020","journal-title":"Biofactors"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1093\/cvr\/cvr147","article-title":"Contributions of ACE and mast cell chymase to endogenous angiotensin II generation and leucocyte recruitment in vivo","volume":"92","author":"Company","year":"2011","journal-title":"Cardiovasc. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"179","DOI":"10.21103\/Article12(2)_RA1","article-title":"Possible Unexplored Aspects of Covid-19 Pathogenesis: The Role of Carboxypeptidase A3","volume":"12","author":"Budnevsky","year":"2022","journal-title":"Int. J. Biomed."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"17","DOI":"10.18093\/0869-0189-2023-33-1-17-26","article-title":"The role of mast cells and their proteases in lung damage associated with COVID-19","volume":"33","author":"Budnevsky","year":"2023","journal-title":"Pul\u2019monologiya"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"574862","DOI":"10.3389\/fimmu.2020.574862","article-title":"Mast cells in alveolar septa of COVID-19 patients: A pathogenic pathway that may link interstitial edema to immunothrombosis","volume":"11","author":"Miggiolaro","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/j.chom.2020.04.017","article-title":"Heightened innate immune responses in the respiratory tract of COVID-19 patients","volume":"27","author":"Zhou","year":"2020","journal-title":"Cell. Host. Microbe"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"650331","DOI":"10.3389\/fimmu.2021.650331","article-title":"Mast cell and eosinophil activation are associated with COVID-19 and TLR-mediated viral inflammation: Implications for an Anti-Siglec-8 antibody","volume":"12","author":"Gebremeskel","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Tan, J., Anderson, D.E., Rathore, A.P.S., O\u2019Neill, A., Mantri, C.K., Saron, W.A.A., Lee, C., Cui, C.W., Kang, A.E.Z., and Foo, R. (2021). Signatures of mast cell activation are associated with severe COVID-19. MedRxiv.","DOI":"10.1101\/2021.05.31.21255594"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1111\/1346-8138.13234","article-title":"Mast cell chymase in experimentally induced psoriasis","volume":"43","author":"Suttle","year":"2016","journal-title":"J. Dermatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1161\/CIRCRESAHA.117.310978","article-title":"Multifunctional role of chymase in acute and chronic tissue injury and remodeling","volume":"122","author":"Collawn","year":"2018","journal-title":"Circ. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1002\/JLB.4HI0221-087R","article-title":"Severe COVID-19 is marked by dysregulated serum levels of carboxypeptidase A3 and serotonin","volume":"110","year":"2021","journal-title":"J. Leukoc. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1159\/000081304","article-title":"Mast cell tryptase activates peripheral blood eosinophils to release granule-associated enzymes","volume":"135","author":"Vliagoftis","year":"2004","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.jaci.2010.04.009","article-title":"Involvement of mast cells in eosinophilic esophagitis","volume":"126","author":"Abonia","year":"2010","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1016\/j.jaci.2010.03.003","article-title":"Accumulation of intraepithelial mast cells with a unique protease phenotype in T(H)2-high asthma","volume":"125","author":"Dougherty","year":"2010","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/j.jaci.2012.02.046","article-title":"Glandular mast cells with distinct phenotype are highly elevated in chronic rhinosinusitis with nasal polyps","volume":"130","author":"Takabayashi","year":"2012","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"118102","DOI":"10.1016\/j.lfs.2020.118102","article-title":"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","volume":"257","author":"Jafarzadeh","year":"2020","journal-title":"Life Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4455","DOI":"10.1021\/acs.jproteome.0c00606","article-title":"Evidence of Structural Protein Damage and Membrane Lipid Remodeling in Red Blood Cells from COVID-19 Patients","volume":"19","author":"Thomas","year":"2020","journal-title":"J. Proteome Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Palladino, M. (2021). Complete blood count alterations in COVID-19 patients: A narrative review. Biochem. Med., 31.","DOI":"10.11613\/BM.2021.030501"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"7834","DOI":"10.1074\/jbc.M111.325712","article-title":"Mast cell restricted mouse and human tryptase\u00b7heparin complexes hinder thrombin-induced coagulation of plasma and the generation of fibrin by proteolytically destroying fibrinogen","volume":"287","author":"Zheng","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"225","DOI":"10.3390\/hematolrep15020024","article-title":"Risk of Thrombosis during and after a SARS-CoV-2 Infection: Pathogenesis, Diagnostic Approach, and Management","volume":"15","author":"Sutanto","year":"2023","journal-title":"Hematol. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2245","DOI":"10.1016\/j.dsx.2020.11.007","article-title":"D-dimer level is a useful predictor for mortality in patients with COVID-19: Analysis of 483 cases","volume":"14","author":"Soni","year":"2020","journal-title":"Diabetes Metab. Syndr."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/8\/711\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:30:51Z","timestamp":1760106651000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/8\/711"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,19]]},"references-count":29,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2024,4]]}},"alternative-id":["cells13080711"],"URL":"https:\/\/doi.org\/10.3390\/cells13080711","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,19]]}}}