TY - JOUR
T1 - Dysregulation of the kallikrein-kinin system in bronchoalveolar lavage fluid of patients with severe COVID-19
AU - Martens, Caroline P
AU - Van Mol, Pierre
AU - Wauters, Joost
AU - Wauters, Els
AU - Gangnus, Tanja
AU - Noppen, Bernard
AU - Callewaert, Hanne
AU - Feyen, Jean H M
AU - Liesenborghs, Laurens
AU - Heylen, Elisabeth
AU - Jansen, Sander
AU - Pereira, Leydi Carolina Velásquez
AU - Kraisin, Sirima
AU - Guler, Ipek
AU - Engelen, Matthias M
AU - Ockerman, Anna
AU - Van Herck, Anke
AU - Vos, Robin
AU - Vandenbriele, Christophe
AU - Meersseman, Philippe
AU - Hermans, Greet
AU - Wilmer, Alexander
AU - Martinod, Kimberly
AU - Burckhardt, Bjoern B
AU - Vanhove, Marc
AU - Jacquemin, Marc
AU - Verhamme, Peter
AU - Neyts, Johan
AU - Vanassche, Thomas
N1 - FTX; DOAJ; (CC BY-NC-ND 4.0)
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - Angiotensin-Converting Enzyme 2
KW - Bradykinin
KW - Bronchoalveolar Lavage Fluid
KW - COVID-19
KW - Humans
KW - Kallikrein-Kinin System
KW - Kallikreins/metabolism
KW - Peroxidase/metabolism
KW - SARS-CoV-2
KW - Tissue Kallikreins/metabolism
U2 - 10.1016/j.ebiom.2022.104195
DO - 10.1016/j.ebiom.2022.104195
M3 - A1: Web of Science-article
C2 - 35939907
SN - 2352-3964
VL - 83
SP - 104195
JO - EBioMedicine
JF - EBioMedicine
ER -