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Observational Study
. 2022 Sep:83:104195.
doi: 10.1016/j.ebiom.2022.104195. Epub 2022 Aug 5.

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

Caroline P Martens  1 , Pierre Van Mol  2 , Joost Wauters  3 , Els Wauters  4 , Tanja Gangnus  5 , Bernard Noppen  6 , Hanne Callewaert  6 , Jean H M Feyen  6 , Laurens Liesenborghs  7 , Elisabeth Heylen  8 , Sander Jansen  8 , Leydi Carolina Velásquez Pereira  1 , Sirima Kraisin  1 , Ipek Guler  9 , Matthias M Engelen  10 , Anna Ockerman  11 , Anke Van Herck  12 , Robin Vos  4 , Christophe Vandenbriele  10 , Philippe Meersseman  13 , Greet Hermans  14 , Alexander Wilmer  13 , Kimberly Martinod  1 , Bjoern B Burckhardt  5 , Marc Vanhove  6 , Marc Jacquemin  15 , Peter Verhamme  10 , Johan Neyts  8 , Thomas Vanassche  16
Affiliations
Observational Study

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

Caroline P Martens et al. EBioMedicine. 2022 Sep.

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.

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Conflict of interest statement

Declaration of interests M.V., B.N., H.C., and J.H.M.F. are employees of Oxurion NV. Oxurion NV and KU Leuven LRD submitted a patent on kallikrein inhibitors. K.M. is an inventor on the granted patent US9642822 awarded to Children's Medical Center Corporation covering the targeting of NETs in thrombosis and lung injury and the pending patent WO20180271953A1. She reports issued patent US9642822B2 and pending patents US2019167680A1. K.M. also reports consulting fees from PEEL Therapeutics. She holds a grant from Flanders Research Foundation (FWO) and a Horizon 2020 grant, as well as a grant from the International Society on Thrombosis and Haemostasis. T.V. is a board member and vice-president of the Belgian Society for Thrombosis and Haemostasis. P.V. and T.V. are co-holders of a research chair for clinical research with Trasylol (DAWN-AntiCo). P.V. holds an institutional grant funded by Bayer AG and by BMS/Pfizer. He reports consulting fees from Anthos Therapeutics, Bayer AG, Boehringer,BMS, Pfizer, Daiichi Sankyo, and Portola/Actelion, and honoraria as a speaker from Bayer, BMS, Pfizer, Daiichi Sankyo, and Leo Pharma. P.V. has participated in a DSMB for clinical trials sponsored by Bayer and Boehringer Ingelheim. R.V. and A.V. report participation in advisory board for Takeda and involvement in ERS, ESOT/ECTTA boards. J.W. is a holder of research grants funded by MSD, Pfizer, and Gilead. He reports speakers fees and support for attending meetings from Gilead, MSD, and Pfizer, and participation on an advisory board for Gilead. He has received study medication for clinical trials from MSD. The other authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The kallikrein-kinin system links coagulation and inflammation in COVID-19. The metabolic pathway of bradykinin, Lys-bradykinin and their metabolites. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes downregulation and functional deficiency of angiotensin-converting enzyme 2 (ACE2), which could impair the degradation of kinin peptides that act on bradykinin receptor 1. Excessive activation of bradykinin receptor 1 results in both hyperinflammatory responses and pulmonary edema, whereas factor XII (FXII) activation leads to coagulation activation and provides a feedback loop with activation of the kallikrein-kinin pathway. Aprotinin inhibits plasma and tissue kallikrein, in addition to its in vitro observed antiviral actions. ACE indicates angiotensin-converting enzyme; C-peptidase, carboxypeptidase; IL-1, interleukin-1; N-peptidase, aminopeptidase; TNFα, tumor necrosis factor alpha. This figure was created with BioRender.
Figure 2
Figure 2
Characterization of patient groups. Overview of characterization of patient groups with and without COVID-19 pneumonia to be compared in the different analyses. This figure was created with BioRender.
Figure 3
Figure 3
Levels of kinin peptides in bronchoalveolar lavage fluid from patients with and without COVID-19. Graphs show individual dots representing patient data and bar representing median of each patient group. For graphical representation, data were transformed using the logarithmic transformation. Pairwise comparisons were made between patients with COVID-19 (n = 21) and patients without COVID-19 (n = 19). Median [range] and p-value (Mann-Whitney U test, not corrected for multiple testing) are shown.
Figure 4
Figure 4
Kallikrein hydrolytic activity in bronchoalveolar lavage fluid from patients with and without COVID-19. Graphs show individual dots representing patient data and bar representing median of each patient group. For graphical representation, data were transformed using the logarithmic transformation. Pairwise comparisons were made between patients with COVID-19 (n = 9) and patients without COVID-19 (n = 11). Median [range] and p-value (Mann-Whitney U test, not corrected for multiple testing) are shown.
Figure 5
Figure 5
MPO-DNA complexes in bronchoalveolar lavage fluid from patients with and without COVID-19. Graphs show individual dots representing patient data and bar representing median of each patient group. For graphical representation, data were transformed using the logarithmic transformation. Pairwise comparisons were made between patients with COVID-19 (n = 21) and patients without COVID-19 (n = 19). Median [range] and p-value are shown (Mann-Whitney U test).
See this image and copyright information in PMC

References

    1. Tran BX, Ha GH, Nguyen LH, et al. Studies of novel coronavirus disease 19 (COVID-19) pandemic: a global analysis of literature. Int J Environ Res Public Health. 2020;17(11):1–16. 4095. - PMC - PubMed
    1. Henry BM, Vikse J, Benoit S, Favaloro EJ, Lippi G. Hyperinflammation and derangement of renin-angiotensin-aldosterone system in COVID-19: a novel hypothesis for clinically suspected hypercoagulopathy and microvascular immunothrombosis. Clin Chim Acta. 2020;507:167–173. - PMC - PubMed
    1. van de Veerdonk FL, Netea MG, van Deuren M, et al. Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome. Elife. 2020;9:1–9. 57555. - PMC - PubMed
    1. de Maat S, de Mast Q, Danser AHJ, van de Veerdonk FL, Maas C. Impaired breakdown of bradykinin and its metabolites as a possible cause for pulmonary edema in COVID-19 infection. Semin Thromb Hemost. 2020;46(7):835–837. - PMC - PubMed
    1. Gorlinger K, Dirkmann D, Gandhi A, Simioni P. COVID-19-associated coagulopathy and inflammatory response: what do we know already and what are the knowledge gaps? Anesth Analg. 2020;131(5):1324–1333. - PMC - PubMed

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