COVID-19: A Disease Driven by Protease/Antiprotease Imbalance? A Specific Review Five Years into the Pandemic
Pierpaolo Di Micco,1 Carmine Siniscalchi,2 Egidio Imbalzano,3 Vincenzo Russo,4 Giuseppe Camporese,5 Corrado Lodigiani,6 Tiziana Meschi,2 Alessandro Perrella7 1UOC Medicina Interna, AFO Medica, P.O. Santa Maria delle Grazie, Pozzuoli (NA), ASL Napoli 2 Nord, CAP 80076, Italy; 2Internal Medicine Depar...
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Dove Medical Press
2025-08-01
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| Series: | Infection and Drug Resistance |
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| Online Access: | https://www.dovepress.com/covid-19-a-disease-driven-by-proteaseantiprotease-imbalance-a-specific-peer-reviewed-fulltext-article-IDR |
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| author | Di Micco P Siniscalchi C Imbalzano E Russo V Camporese G Lodigiani C Meschi T Perrella A |
| author_facet | Di Micco P Siniscalchi C Imbalzano E Russo V Camporese G Lodigiani C Meschi T Perrella A |
| author_sort | Di Micco P |
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| description | Pierpaolo Di Micco,1 Carmine Siniscalchi,2 Egidio Imbalzano,3 Vincenzo Russo,4 Giuseppe Camporese,5 Corrado Lodigiani,6 Tiziana Meschi,2 Alessandro Perrella7 1UOC Medicina Interna, AFO Medica, P.O. Santa Maria delle Grazie, Pozzuoli (NA), ASL Napoli 2 Nord, CAP 80076, Italy; 2Internal Medicine Department, Parma University Hospital, Parma, Italy; 3Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; 4Department of Cardiology, Vanvitelli University of Naples, Naples, Italy; 5Department of Internal Medicine DIMED, Padua University Hospital, Padua, Italy; 6Department of Internal Medicine, Humanitas Hospital Milano, Milano, Italy; 7UOC Emerging Infectious Disease and High Contagiousness AORN Ospedale dei Colli-PO D. Cotugno, Naples, ItalyCorrespondence: Pierpaolo Di Micco, UOC Medicina Interna, AFO Medica, P.O. Santa Maria delle Grazie, Pozzuoli (NA), ASL Napoli 2 Nord, CAP 80076, Italy, Email pdimicco@libero.itAbstract: COVID-19, caused by SARS-CoV-2, has profoundly impacted global health since late 2019. Beyond respiratory complications, the disease involves systemic manifestations driven by immune dysregulation, inflammation, and coagulopathy. Among the many mechanisms implicated in severe disease, a growing body of evidence suggests a central role for the imbalance between proteases and antiproteases. This review examines how dysregulated protease activity contributes to viral entry, cytokine activation, vascular injury, and thrombosis. We focus on the integration of proteolytic systems such as the renin-angiotensin system, coagulation cascade, and neutrophil extracellular traps with established pathways like endothelial dysfunction and immune hyperactivation. Furthermore, we highlight therapeutic strategies aimed at restoring proteolytic balance and discuss the potential relevance of this paradigm in the management of long COVID.Keywords: COVID-19, protease-antiprotease balance, cytokine storm, hypercoagulability, fibrinolysis, serpins, inflammation, imaging, biomarkers |
| format | Article |
| id | doaj-art-5c6fd16cb0534f969c266c4bb2cc337f |
| institution | Kabale University |
| issn | 1178-6973 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Infection and Drug Resistance |
| spelling | doaj-art-5c6fd16cb0534f969c266c4bb2cc337f2025-08-20T03:40:25ZengDove Medical PressInfection and Drug Resistance1178-69732025-08-01Volume 18Issue 139673975105608COVID-19: A Disease Driven by Protease/Antiprotease Imbalance? A Specific Review Five Years into the PandemicDi Micco P0Siniscalchi C1Imbalzano E2Russo V3Camporese G4Lodigiani C5Meschi T6Perrella AMedicineInternal Medicine DepartmentDepartment of Clinical and Experimental MedicineDepartment of CardiologyDepartment of Internal Medicine DIMEDCenter for Thrombosis and Hemorrhagic DiseasesInternal Medicine DepartmentPierpaolo Di Micco,1 Carmine Siniscalchi,2 Egidio Imbalzano,3 Vincenzo Russo,4 Giuseppe Camporese,5 Corrado Lodigiani,6 Tiziana Meschi,2 Alessandro Perrella7 1UOC Medicina Interna, AFO Medica, P.O. Santa Maria delle Grazie, Pozzuoli (NA), ASL Napoli 2 Nord, CAP 80076, Italy; 2Internal Medicine Department, Parma University Hospital, Parma, Italy; 3Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; 4Department of Cardiology, Vanvitelli University of Naples, Naples, Italy; 5Department of Internal Medicine DIMED, Padua University Hospital, Padua, Italy; 6Department of Internal Medicine, Humanitas Hospital Milano, Milano, Italy; 7UOC Emerging Infectious Disease and High Contagiousness AORN Ospedale dei Colli-PO D. Cotugno, Naples, ItalyCorrespondence: Pierpaolo Di Micco, UOC Medicina Interna, AFO Medica, P.O. Santa Maria delle Grazie, Pozzuoli (NA), ASL Napoli 2 Nord, CAP 80076, Italy, Email pdimicco@libero.itAbstract: COVID-19, caused by SARS-CoV-2, has profoundly impacted global health since late 2019. Beyond respiratory complications, the disease involves systemic manifestations driven by immune dysregulation, inflammation, and coagulopathy. Among the many mechanisms implicated in severe disease, a growing body of evidence suggests a central role for the imbalance between proteases and antiproteases. This review examines how dysregulated protease activity contributes to viral entry, cytokine activation, vascular injury, and thrombosis. We focus on the integration of proteolytic systems such as the renin-angiotensin system, coagulation cascade, and neutrophil extracellular traps with established pathways like endothelial dysfunction and immune hyperactivation. Furthermore, we highlight therapeutic strategies aimed at restoring proteolytic balance and discuss the potential relevance of this paradigm in the management of long COVID.Keywords: COVID-19, protease-antiprotease balance, cytokine storm, hypercoagulability, fibrinolysis, serpins, inflammation, imaging, biomarkershttps://www.dovepress.com/covid-19-a-disease-driven-by-proteaseantiprotease-imbalance-a-specific-peer-reviewed-fulltext-article-IDRCOVID-19protease-antiprotease balancecytokine stormhypercoagulabilityfibrinolysisserpins |
| spellingShingle | Di Micco P Siniscalchi C Imbalzano E Russo V Camporese G Lodigiani C Meschi T Perrella A COVID-19: A Disease Driven by Protease/Antiprotease Imbalance? A Specific Review Five Years into the Pandemic Infection and Drug Resistance COVID-19 protease-antiprotease balance cytokine storm hypercoagulability fibrinolysis serpins |
| title | COVID-19: A Disease Driven by Protease/Antiprotease Imbalance? A Specific Review Five Years into the Pandemic |
| title_full | COVID-19: A Disease Driven by Protease/Antiprotease Imbalance? A Specific Review Five Years into the Pandemic |
| title_fullStr | COVID-19: A Disease Driven by Protease/Antiprotease Imbalance? A Specific Review Five Years into the Pandemic |
| title_full_unstemmed | COVID-19: A Disease Driven by Protease/Antiprotease Imbalance? A Specific Review Five Years into the Pandemic |
| title_short | COVID-19: A Disease Driven by Protease/Antiprotease Imbalance? A Specific Review Five Years into the Pandemic |
| title_sort | covid 19 a disease driven by protease antiprotease imbalance a specific review five years into the pandemic |
| topic | COVID-19 protease-antiprotease balance cytokine storm hypercoagulability fibrinolysis serpins |
| url | https://www.dovepress.com/covid-19-a-disease-driven-by-proteaseantiprotease-imbalance-a-specific-peer-reviewed-fulltext-article-IDR |
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