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.
【저자키워드】 SARS-CoV-2, Thromboinflammation, extracellular traps, Kinins, Kallikreins, 【초록키워드】 COVID-19, ACE2, coronavirus, Biomarker, severe COVID-19, peptide, angiotensin-converting enzyme 2, COVID, BAL, Research, Patient, peptides, Neutrophil extracellular trap, plasma, Coagulation system, receptor, Critical, funding, NETs, myeloperoxidase, Bronchoalveolar lavage, Hypothesis, Kallikrein-kinin system, dysregulation, Support, observation, acute respiratory syndrome, tissue, hydrolytic activity, potential treatment option, help, severe pulmonary disease, mechanically ventilated, finding, thromboembolic complications, oedema, increased vascular permeability, BAL fluid, inflammatory chemokines, bind, median, contribute, occur, complexes, explain, kallikrein-kinin, Leuven, mechanically ventilated patient, patients without COVID-19, thromboembolic complication, 【제목키워드】 severe COVID-19, Bronchoalveolar lavage fluid, Patient, Kallikrein-kinin system,