{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:13:42Z","timestamp":1760145222825,"version":"build-2065373602"},"reference-count":274,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2024,7,10]],"date-time":"2024-07-10T00:00:00Z","timestamp":1720569600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Proteases are produced and released in the mucosal cells of the respiratory tract and have important physiological functions, for example, maintaining airway humidification to allow proper gas exchange. The infectious mechanism of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), takes advantage of host proteases in two ways: to change the spatial conformation of the spike (S) protein via endoproteolysis (e.g., transmembrane serine protease type 2 (TMPRSS2)) and as a target to anchor to epithelial cells (e.g., angiotensin-converting enzyme 2 (ACE2)). This infectious process leads to an imbalance in the mucosa between the release and action of proteases versus regulation by anti-proteases, which contributes to the exacerbation of the inflammatory and prothrombotic response in COVID-19. In this article, we describe the most important proteases that are affected in COVID-19, and how their overactivation affects the three main physiological systems in which they participate: the complement system and the kinin\u2013kallikrein system (KKS), which both form part of the contact system of innate immunity, and the renin\u2013angiotensin\u2013aldosterone system (RAAS). We aim to elucidate the pathophysiological bases of COVID-19 in the context of the imbalance between the action of proteases and anti-proteases to understand the mechanism of aprotinin action (a panprotease inhibitor). In a second-part review, titled \u201cAprotinin (II): Inhalational Administration for the Treatment of COVID-19 and Other Viral Conditions\u201d, we explain in depth the pharmacodynamics, pharmacokinetics, toxicity, and use of aprotinin as an antiviral drug.<\/jats:p>","DOI":"10.3390\/ijms25147553","type":"journal-article","created":{"date-parts":[[2024,7,10]],"date-time":"2024-07-10T09:23:08Z","timestamp":1720603388000},"page":"7553","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Aprotinin (I): Understanding the Role of Host Proteases in COVID-19 and the Importance of Pharmacologically Regulating Their Function"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4585-9401","authenticated-orcid":false,"given":"Juan Fernando","family":"Pad\u00edn","sequence":"first","affiliation":[{"name":"Department of Medical Sciences, School of Medicine at Ciudad Real, University of Castilla-La Mancha, 13971 Ciudad Real, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3588-6273","authenticated-orcid":false,"given":"Jos\u00e9 Manuel","family":"P\u00e9rez-Ortiz","sequence":"additional","affiliation":[{"name":"Facultad HM de Ciencias de la Salud, Universidad Camilo Jos\u00e9 Cela, 28692 Madrid, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria HM Hospitales, 28015 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7044-0154","authenticated-orcid":false,"given":"Francisco Javier","family":"Redondo-Calvo","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, School of Medicine at Ciudad Real, University of Castilla-La Mancha, 13971 Ciudad Real, Spain"},{"name":"Department of Anaesthesiology and Critical Care Medicine, University General Hospital, 13005 Ciudad Real, Spain"},{"name":"Translational Research Unit, University General Hospital and Research Institute of Castilla-La Mancha (IDISCAM), 13005 Ciudad Real, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Pad\u00edn, J.-F., P\u00e9rez-Ortiz, J.M., and Redondo-Calvo, F.J. 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