Dysregulation of the kallikrein-kinin system in bronchoalveolar lavage fluid of patients with severe COVID-19

Martens, Caroline; Van Mol, Pierre; Wauters, Joost; Wauters, Els; Gangnus, Tanja; Noppen, Bernard; Callewaert, Hanne; Feyen, Jean HM; Liesenborghs, Laurens; Heylen, Elisabeth; Jansen, Sander; Velásquez Pereira, Leydi Carolina; Kraisin, Sirima; Guler Caamano Fajardo, Ipek; Engelen, Matthias; Ockerman, Anna; Van Herck, Anke; Vos, Robin; Vandenbriele, Christophe; Meersseman, Philippe; Hermans, Greet; Wilmer, Peter Alexander; Martinod, Kimberley; Burckhardt, Bjoern B; Vanhove, Marc; Jacquemin, Marc; Verhamme, Peter; Neyts, J; Vanassche, Thomas

doi:10.1016/j.ebiom.2022.104195

Dysregulation of the kallikrein-kinin system in bronchoalveolar lavage fluid of patients with severe COVID-19

Author:

Martens, Caroline

Van Mol, Pierre ; Wauters, Joost ; Wauters, Els ; Gangnus, Tanja ; Noppen, Bernard ; Callewaert, Hanne ; Feyen, Jean HM ; Liesenborghs, Laurens ; Heylen, Elisabeth ; Jansen, Sander ; Velásquez Pereira, Leydi Carolina ; Kraisin, Sirima ; Guler Caamano Fajardo, Ipek ; Engelen, Matthias ; Ockerman, Anna ; Van Herck, Anke ; Vos, Robin ; Vandenbriele, Christophe ; Meersseman, Philippe ; Hermans, Greet ; Wilmer, Peter Alexander ; Martinod, Kimberley ; Burckhardt, Bjoern B ; Vanhove, Marc ; Jacquemin, Marc ; Verhamme, Peter ; Neyts, J ; Vanassche, Thomas

Keywords:

Extracellular traps, Kallikreins, Kinins, SARS-CoV-2, Thromboinflammation, Science & Technology, Life Sciences & Biomedicine, Medicine, General & Internal, Medicine, Research & Experimental, General & Internal Medicine, Research & Experimental Medicine, IN-VITRO, ACTIVATION, ACE2, COAGULATION, DNA, Angiotensin-Converting Enzyme 2, Bradykinin, Bronchoalveolar Lavage Fluid, COVID-19, Humans, Kallikrein-Kinin System, Peroxidase, Tissue Kallikreins, 1S66020N|1S66022N#55246106, C24M/20/056#55737123, 1805121N#56524807, 11B0621N|11B0623N#55771697, G0G4720N#55954743, 1803521N#56522477, 1103 Clinical Sciences, 1117 Public Health and Health Services, 3202 Clinical sciences, 4202 Epidemiology

Abstract:

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.