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 MeerssemanGreet Hermans, Alexander Wilmer, Kimberly Martinod, Bjoern B Burckhardt, Marc Vanhove, Marc Jacquemin, Peter Verhamme, Johan Neyts, Thomas Vanassche

Research output: Contribution to journalA1: Web of Science-articlepeer-review

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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.

Original languageEnglish
Pages (from-to)104195
Publication statusPublished - 2022


  • Angiotensin-Converting Enzyme 2
  • Bradykinin
  • Bronchoalveolar Lavage Fluid
  • COVID-19
  • Humans
  • Kallikrein-Kinin System
  • Kallikreins/metabolism
  • Peroxidase/metabolism
  • SARS-CoV-2
  • Tissue Kallikreins/metabolism


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