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      Dysregulation of the kallikrein-kinin system in bronchoalveolar lavage fluid of patients with severe COVID-19

      research-article
      Author(s): a , 1 , b , c , 1 , d , e , c , f , g , h , h , h , a , i , j , i , i , a , a , a , k , a , l , m , f , c , f , a , l , d , d , n , d , a , g , h , a , o , a , l , i , a , l , *
      Publication date (Electronic):
      Journal: eBioMedicine
      Publisher: The Authors. Published by Elsevier B.V.
      Keywords: SARS-CoV-2, Kallikreins, Kinins, Extracellular traps, Thromboinflammation

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          Abstract

          Background

          Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the angiotensin-converting enzyme 2 (ACE2) receptor, a critical component of the kallikrein-kinin system. Its dysregulation may lead to increased vascular permeability and release of inflammatory chemokines. Interactions between the kallikrein-kinin and the coagulation system might further contribute to thromboembolic complications in COVID-19.

          Methods

          In this observational study, we measured plasma and tissue kallikrein hydrolytic activity, levels of kinin peptides, and myeloperoxidase (MPO)-DNA complexes as a biomarker for neutrophil extracellular traps (NETs), in bronchoalveolar lavage (BAL) fluid from patients with and without COVID-19.

          Findings

          In BAL fluid from patients with severe COVID-19 ( n = 21, of which 19 were mechanically ventilated), we observed higher tissue kallikrein activity (18·2 pM [1·2-1535·0], median [range], n = 9 vs 3·8 [0·0-22·0], n = 11; p = 0·030), higher levels of the kinin peptide bradykinin-(1-5) (89·6 [0·0-2425·0], n = 21 vs 0·0 [0·0-374·0], n = 19, p = 0·001), and higher levels of MPO-DNA complexes (699·0 ng/mL [66·0-142621·0], n = 21 vs 70·5 [9·9-960·0], n = 19, p < 0·001) compared to patients without COVID-19.

          Interpretation

          Our observations support the hypothesis that dysregulation of the kallikrein-kinin system might occur in mechanically ventilated patients with severe pulmonary disease, which might help to explain the clinical presentation of patients with severe COVID-19 developing pulmonary oedema and thromboembolic complications. Therefore, targeting the kallikrein-kinin system should be further explored as a potential treatment option for patients with severe COVID-19.

          Funding

          Research Foundation-Flanders (G0G4720N, 1843418N), KU Leuven COVID research fund.

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          Most cited references45

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          Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

          Yoav Benjamini, Yosef Hochberg (1995)
          Article 0 comments Cited 23619 times – based on 0 reviews     Review now
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            SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

            Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder … (2020)
            Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.
            Article 0 comments Cited 9619 times – based on 0 reviews     Review now
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              A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury

              Keiji Kuba, Yumiko Imai, Shuan Rao … (2005)
              During several months of 2003, a newly identified illness termed severe acute respiratory syndrome (SARS) spread rapidly through the world 1,2,3 . A new coronavirus (SARS-CoV) was identified as the SARS pathogen 4,5,6,7 , which triggered severe pneumonia and acute, often lethal, lung failure 8 . Moreover, among infected individuals influenza such as the Spanish flu 9,10 and the emergence of new respiratory disease viruses 11,12 have caused high lethality resulting from acute lung failure 13 . In cell lines, angiotensin-converting enzyme 2 (ACE2) has been identified as a potential SARS-CoV receptor 14 . The high lethality of SARS-CoV infections, its enormous economic and social impact, fears of renewed outbreaks as well as the potential misuse of such viruses as biologic weapons make it paramount to understand the pathogenesis of SARS-CoV. Here we provide the first genetic proof that ACE2 is a crucial SARS-CoV receptor in vivo. SARS-CoV infections and the Spike protein of the SARS-CoV reduce ACE2 expression. Notably, injection of SARS-CoV Spike into mice worsens acute lung failure in vivo that can be attenuated by blocking the renin-angiotensin pathway. These results provide a molecular explanation why SARS-CoV infections cause severe and often lethal lung failure and suggest a rational therapy for SARS and possibly other respiratory disease viruses. Supplementary information The online version of this article (doi:10.1038/nm1267) contains supplementary material, which is available to authorized users.
              Article 0 comments Cited 1292 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): eBioMedicine
                Journal ID (iso-abbrev): EBioMedicine
                Title: eBioMedicine
                Publisher: The Authors. Published by Elsevier B.V.
                ISSN (Electronic): 2352-3964
                Publication date PMC-release: 5 August 2022
                Publication date (Print): September 2022
                Publication date (Electronic): 5 August 2022
                Volume: 83
                Page: 104195
                Affiliations
                [a ]Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium
                [b ]Laboratory for Translational Genetics, VIB – KU Leuven, Leuven, Belgium
                [c ]Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium
                [d ]Medical Intensive Care Unit, Department of General Internal Medicine, University Hospitals Leuven, Leuven, Belgium
                [e ]Laboratory for Clinical Infectious and Inflammatory Diseases, Department of Microbiology and Immunity, KU Leuven, Leuven, Belgium
                [f ]Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
                [g ]Institute of Clinical Pharmacy and Pharmacotherapy, Heinrich Heine University, Düsseldorf, Germany
                [h ]Oxurion NV, Leuven, Belgium
                [i ]Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium
                [j ]The Outbreak Research Team, Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium
                [k ]Leuven Biostatistics and Statistical Bioinformatics Centre (L-BioStat), KU Leuven, Leuven, Belgium
                [l ]Department of Cardiovascular Diseases, University Hospitals Leuven, Leuven, Belgium
                [m ]Oral and Maxillofacial Surgery - Imaging & Pathology Research Group, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
                [n ]Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
                [o ]Clinical Department of Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium
                Author notes
                [* ]Corresponding author.
                [1]

                These authors share first authorship.

                Article
                Publisher Item ID: S2352-3964(22)00377-2 Publisher ID: 104195
                DOI: 10.1016/j.ebiom.2022.104195
                PMC ID: 9352453
                PubMed ID: 35939907
                SO-VID: cbdd0e7d-4831-4661-b8ee-30ec6c61585e
                Copyright © © 2022 The Authors
                License:

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                Date received : 7 June 2021
                Date revision received : 6 July 2022
                Date accepted : 15 July 2022
                Categories
                Subject: Articles

                Keywords: sars-cov-2,kallikreins,kinins,extracellular traps,thromboinflammation
                Data availability:
                Keywords: sars-cov-2, kallikreins, kinins, extracellular traps, thromboinflammation

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