tetano
Editor, Senior Moderator
EBioMedicine
. 2022 Aug 5;83:104195.
doi: 10.1016/j.ebiom.2022.104195. Online ahead of print.
Dysregulation of the kallikrein-kinin system in bronchoalveolar lavage fluid of patients with severe COVID-19
Caroline P Martens[SUP] 1 [/SUP], Pierre Van Mol[SUP] 2 [/SUP], Joost Wauters[SUP] 3 [/SUP], Els Wauters[SUP] 4 [/SUP], Tanja Gangnus[SUP] 5 [/SUP], Bernard Noppen[SUP] 6 [/SUP], Hanne Callewaert[SUP] 6 [/SUP], Jean H M Feyen[SUP] 6 [/SUP], Laurens Liesenborghs[SUP] 7 [/SUP], Elisabeth Heylen[SUP] 8 [/SUP], Sander Jansen[SUP] 8 [/SUP], Leydi Carolina Velásquez Pereira[SUP] 1 [/SUP], Sirima Kraisin[SUP] 1 [/SUP], Ipek Guler[SUP] 9 [/SUP], Matthias M Engelen[SUP] 10 [/SUP], Anna Ockerman[SUP] 11 [/SUP], Anke Van Herck[SUP] 12 [/SUP], Robin Vos[SUP] 4 [/SUP], Christophe Vandenbriele[SUP] 10 [/SUP], Philippe Meersseman[SUP] 13 [/SUP], Greet Hermans[SUP] 14 [/SUP], Alexander Wilmer[SUP] 13 [/SUP], Kimberly Martinod[SUP] 1 [/SUP], Bjoern B Burckhardt[SUP] 5 [/SUP], Marc Vanhove[SUP] 6 [/SUP], Marc Jacquemin[SUP] 15 [/SUP], Peter Verhamme[SUP] 10 [/SUP], Johan Neyts[SUP] 8 [/SUP], Thomas Vanassche[SUP] 16 [/SUP]
Affiliations
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.
Keywords: Extracellular traps; Kallikreins; Kinins; SARS-CoV-2; Thromboinflammation.
. 2022 Aug 5;83:104195.
doi: 10.1016/j.ebiom.2022.104195. Online ahead of print.
Dysregulation of the kallikrein-kinin system in bronchoalveolar lavage fluid of patients with severe COVID-19
Caroline P Martens[SUP] 1 [/SUP], Pierre Van Mol[SUP] 2 [/SUP], Joost Wauters[SUP] 3 [/SUP], Els Wauters[SUP] 4 [/SUP], Tanja Gangnus[SUP] 5 [/SUP], Bernard Noppen[SUP] 6 [/SUP], Hanne Callewaert[SUP] 6 [/SUP], Jean H M Feyen[SUP] 6 [/SUP], Laurens Liesenborghs[SUP] 7 [/SUP], Elisabeth Heylen[SUP] 8 [/SUP], Sander Jansen[SUP] 8 [/SUP], Leydi Carolina Velásquez Pereira[SUP] 1 [/SUP], Sirima Kraisin[SUP] 1 [/SUP], Ipek Guler[SUP] 9 [/SUP], Matthias M Engelen[SUP] 10 [/SUP], Anna Ockerman[SUP] 11 [/SUP], Anke Van Herck[SUP] 12 [/SUP], Robin Vos[SUP] 4 [/SUP], Christophe Vandenbriele[SUP] 10 [/SUP], Philippe Meersseman[SUP] 13 [/SUP], Greet Hermans[SUP] 14 [/SUP], Alexander Wilmer[SUP] 13 [/SUP], Kimberly Martinod[SUP] 1 [/SUP], Bjoern B Burckhardt[SUP] 5 [/SUP], Marc Vanhove[SUP] 6 [/SUP], Marc Jacquemin[SUP] 15 [/SUP], Peter Verhamme[SUP] 10 [/SUP], Johan Neyts[SUP] 8 [/SUP], Thomas Vanassche[SUP] 16 [/SUP]
Affiliations
- PMID: 35939907
- DOI: 10.1016/j.ebiom.2022.104195
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.
Keywords: Extracellular traps; Kallikreins; Kinins; SARS-CoV-2; Thromboinflammation.