Dysregulation of the kallikrein-kinin system in bronchoalveolar lavage fluid of patients with severe COVID-19
Caroline P. Martens,
Pierre Van Mol,
Joost Wauters,
Els Wauters,
Tanja Gangnus,
Bernard Noppen,
Hanne Callewaert,
Jean H.M. Feyen,
Laurens Liesenborghs,
Elisabeth Heylen,
Sander Jansen,
Leydi Carolina Velásquez Pereira,
Sirima Kraisin,
Ipek Guler,
Matthias M. Engelen,
Anna Ockerman,
Anke Van Herck,
Robin Vos,
Christophe Vandenbriele,
Philippe Meersseman,
Greet Hermans,
Alexander Wilmer,
Kimberly Martinod,
Bjoern B. Burckhardt,
Marc Vanhove,
Marc Jacquemin,
Peter Verhamme,
Johan Neyts,
Thomas Vanassche
Affiliations
Caroline P. Martens
Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium
Pierre Van Mol
Laboratory for Translational Genetics, VIB – KU Leuven, Leuven, Belgium; Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium
Joost Wauters
Medical Intensive Care Unit, Department of General Internal Medicine, University Hospitals Leuven, Leuven, Belgium; Laboratory for Clinical Infectious and Inflammatory Diseases, Department of Microbiology and Immunity, KU Leuven, Leuven, Belgium
Els Wauters
Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium; Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
Tanja Gangnus
Institute of Clinical Pharmacy and Pharmacotherapy, Heinrich Heine University, Düsseldorf, Germany
Bernard Noppen
Oxurion NV, Leuven, Belgium
Hanne Callewaert
Oxurion NV, Leuven, Belgium
Jean H.M. Feyen
Oxurion NV, Leuven, Belgium
Laurens Liesenborghs
Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium; Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium; The Outbreak Research Team, Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium
Elisabeth Heylen
Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium
Sander Jansen
Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium
Leydi Carolina Velásquez Pereira
Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium
Sirima Kraisin
Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium
Ipek Guler
Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium; Leuven Biostatistics and Statistical Bioinformatics Centre (L-BioStat), KU Leuven, Leuven, Belgium
Matthias M. Engelen
Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium; Department of Cardiovascular Diseases, University Hospitals Leuven, Leuven, Belgium
Anna Ockerman
Oral and Maxillofacial Surgery - Imaging & Pathology Research Group, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
Anke Van Herck
Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
Robin Vos
Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium; Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
Christophe Vandenbriele
Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium; Department of Cardiovascular Diseases, University Hospitals Leuven, Leuven, Belgium
Philippe Meersseman
Medical Intensive Care Unit, Department of General Internal Medicine, University Hospitals Leuven, Leuven, Belgium
Greet Hermans
Medical Intensive Care Unit, Department of General Internal Medicine, University Hospitals Leuven, Leuven, Belgium; Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
Alexander Wilmer
Medical Intensive Care Unit, Department of General Internal Medicine, University Hospitals Leuven, Leuven, Belgium
Kimberly Martinod
Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium
Bjoern B. Burckhardt
Institute of Clinical Pharmacy and Pharmacotherapy, Heinrich Heine University, Düsseldorf, Germany
Marc Vanhove
Oxurion NV, Leuven, Belgium
Marc Jacquemin
Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium; Clinical Department of Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium
Peter Verhamme
Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium; Department of Cardiovascular Diseases, University Hospitals Leuven, Leuven, Belgium
Johan Neyts
Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium
Thomas Vanassche
Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium; Department of Cardiovascular Diseases, University Hospitals Leuven, Leuven, Belgium; Corresponding author.
Summary: 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.
