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Dysregulation of the kallikrein-kinin system in bronchoalveolar lavage fluid of patients with severe COVID-19.
Martens, Caroline P; Van Mol, Pierre; Wauters, Joost; Wauters, Els; Gangnus, Tanja; Noppen, Bernard; Callewaert, Hanne; Feyen, Jean H M; Liesenborghs, Laurens; Heylen, Elisabeth; Jansen, Sander; Pereira, Leydi Carolina Velásquez; Kraisin, Sirima; Guler, Ipek; Engelen, Matthias M; Ockerman, Anna; Van Herck, Anke; Vos, Robin; Vandenbriele, Christophe; Meersseman, Philippe; Hermans, Greet; Wilmer, Alexander; Martinod, Kimberly; Burckhardt, Bjoern B; Vanhove, Marc; Jacquemin, Marc; Verhamme, Peter; Neyts, Johan; Vanassche, Thomas.
  • Martens CP; Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium.
  • Van Mol P; Laboratory for Translational Genetics, VIB - KU Leuven, Leuven, Belgium; Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium.
  • Wauters J; 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.
  • Wauters E; 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.
  • Gangnus T; Institute of Clinical Pharmacy and Pharmacotherapy, Heinrich Heine University, Düsseldorf, Germany.
  • Noppen B; Oxurion NV, Leuven, Belgium.
  • Callewaert H; Oxurion NV, Leuven, Belgium.
  • Feyen JHM; Oxurion NV, Leuven, Belgium.
  • Liesenborghs L; 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 Cli
  • Heylen E; Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium.
  • Jansen S; Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium.
  • Pereira LCV; Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium.
  • Kraisin S; Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium.
  • Guler I; 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.
  • Engelen MM; Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium; Department of Cardiovascular Diseases, University Hospitals Leuven, Leuven, Belgium.
  • Ockerman A; Oral and Maxillofacial Surgery - Imaging & Pathology Research Group, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium.
  • Van Herck A; Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium.
  • Vos R; 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.
  • Vandenbriele C; Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium; Department of Cardiovascular Diseases, University Hospitals Leuven, Leuven, Belgium.
  • Meersseman P; Medical Intensive Care Unit, Department of General Internal Medicine, University Hospitals Leuven, Leuven, Belgium.
  • Hermans G; 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.
  • Wilmer A; Medical Intensive Care Unit, Department of General Internal Medicine, University Hospitals Leuven, Leuven, Belgium.
  • Martinod K; Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium.
  • Burckhardt BB; Institute of Clinical Pharmacy and Pharmacotherapy, Heinrich Heine University, Düsseldorf, Germany.
  • Vanhove M; Oxurion NV, Leuven, Belgium.
  • Jacquemin M; Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium; Clinical Department of Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium.
  • Verhamme P; Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium; Department of Cardiovascular Diseases, University Hospitals Leuven, Leuven, Belgium.
  • Neyts J; Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium.
  • Vanassche T; Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium; Department of Cardiovascular Diseases, University Hospitals Leuven, Leuven, Belgium. Electronic address: thomas.vanassche@uzleuven.be.
EBioMedicine ; 83: 104195, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-2035960
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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Full text: Available Collection: International databases Database: MEDLINE Main subject: Kallikrein-Kinin System / COVID-19 Type of study: Observational study / Prognostic study Limits: Humans Language: English Journal: EBioMedicine Year: 2022 Document Type: Article Affiliation country: J.ebiom.2022.104195

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Kallikrein-Kinin System / COVID-19 Type of study: Observational study / Prognostic study Limits: Humans Language: English Journal: EBioMedicine Year: 2022 Document Type: Article Affiliation country: J.ebiom.2022.104195