Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome

Frank L van de Veerdonk, Mihai G Netea, Marcel van Deuren, Jos Wm van der Meer, Quirijn de Mast, Roger J Brüggemann, Hans van der Hoeven, Frank L van de Veerdonk, Mihai G Netea, Marcel van Deuren, Jos Wm van der Meer, Quirijn de Mast, Roger J Brüggemann, Hans van der Hoeven

Abstract

COVID-19 patients can present with pulmonary edema early in disease. We propose that this is due to a local vascular problem because of activation of bradykinin 1 receptor (B1R) and B2R on endothelial cells in the lungs. SARS-CoV-2 enters the cell via ACE2 that next to its role in RAAS is needed to inactivate des-Arg9 bradykinin, the potent ligand of the B1R. Without ACE2 acting as a guardian to inactivate the ligands of B1R, the lung environment is prone for local vascular leakage leading to angioedema. Here, we hypothesize that a kinin-dependent local lung angioedema via B1R and eventually B2R is an important feature of COVID-19. We propose that blocking the B2R and inhibiting plasma kallikrein activity might have an ameliorating effect on early disease caused by COVID-19 and might prevent acute respiratory distress syndrome (ARDS). In addition, this pathway might indirectly be responsive to anti-inflammatory agents.

Keywords: COVID-19; SARS; bradykinin; human biology; icatibant; immunology; inflammation; kinin; medicine; virus.

Conflict of interest statement

Fv, MN, Mv, Qd, RB, Hv No competing interests declared, Jv Senior editor, eLife

© 2020, van de Veerdonk et al.

Figures

Figure 1.. The kinin-kallikrein system and ACE/ACE2.
Figure 1.. The kinin-kallikrein system and ACE/ACE2.
The pathways of processing of low-molecular-weight kininogen (LMWK) and high-molecular-weight kallikrein (HMWK) leading to Bradykinin 1 (B1) receptor agonists and Bradykinin 2 (B2) receptor agonists. CPM = carboxypeptidaseM; CPN = carboxypeptidaseN.
Figure 2.. Schematic view of treatment strategies…
Figure 2.. Schematic view of treatment strategies in COVID-19.
Figure 3.. Alveolus in normal setting and…
Figure 3.. Alveolus in normal setting and during moderate and severe COVID-19, (A) normal, (B) mild inflammation, (C) hyperinflammation.
ACE2 downregulation by the SARS-CoV-2 is followed by loss of neutralizing capacity of Lys-des-arg9-bradykinin (BK) in the lung leading to plasma leakage. Subsequently plasma leakage results in more B1R ligands (des-arg9-BK) and B2R ligands (bradykinin).

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Source: PubMed

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