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

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.

Interferons and viruses induce a novel primate-specific isoform dACE2 and not the SARS-CoV-2 receptor ACE2

“…Although possible ISG-type ACE2 induction was considered as a risk for increasing SARS-CoV-2 infection, ACE2 deficiency rather than overexpression is discussed as a major factor contributing to COVID-19 morbidity [12][13][14]32 . Functional ACE2 deficiency occurs due to internalization of the SARS-CoV-2 -ACE2 complex 2,33 , which restricts ACE2 from performing its physiological functions, including its role as carboxypeptidase for angiotensin II and des-Arg9-bradykinin and other peptide hormones.…”

“…ACE and ACE2 belong to the renin-angiotensin-aldosterone system, which regulates blood pressure and fluid-electrolyte balance; dysfunction of this system contributes to comorbidities in COVID-19 10,12 . des-Arg9-bradykinin is generated from bradykinin and belongs to the kallikrein-kinin system, which is critical in regulating vascular leakage and pulmonary edema, early signs of severe COVID-19 13,14 .…”

High affinity binding of SARS-CoV-2 spike protein enhances ACE2 carboxypeptidase activity

“…ACE deactivates Bradykinin nonapeptide, the ligand for constitutively expressed bradykinin receptor B2. Bradykinin can be further processed by carboxypeptidase N or M to form des-Arg9-bradykinin, which is a potent ligand for inflammation-inducible bradykinin receptor B1 15 . Beyond Renin-angiotensin and kinin-kallikrein systems, ACE2 also cleaves other biological peptides such as Apelin-13 that activates apelin receptor to cause vasodilatation.…”

Immunomodulatory Therapeutic Proteins in COVID‐19: Current Clinical Development and Clinical Pharmacology Considerations

“…Binding of bradykinin to the B2R on endothelial cells can lead to capillary leakage, which causess angioedema. 72 Van de Veerdonk proposed that kallikrein-kinin blockade may have the potential to prevent ARDS in patients with COVID-19. Lanadelumab, a human monoclonal antibody targeting plasma kallikrein, was approved to prevent angioedema in patients with hereditary angioedema.…”