COVID-19 patients can present with pulmonary edema early in disease. We propose that the 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 RAS is needed to inactivate des-Arg9 bradykinin, the potent ligand of the bradykinin receptor type 1 (B1). Without ACE2 acting as a guardian to inactivate the ligands of B1, the lung environment is prone for local vascular leakage leading to angioedema. Here we hypothesize that a bradykinin-dependent local lung angioedema via B1 and B2 receptors is an important feature of COVID-19. We propose that blocking the B2 receptor and inhibiting 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.
Associated Clinical Trials
Kinin B1 receptor up-regulation after lipopolysaccharide administration: role of proinflammatory cytokines and neutrophil influx
Development of orally bioavailable and CNS penetrant biphenylaminocyclopropane carboxamide bradykinin B1 receptor antagonists
Differential downregulation of ACE2 by the spike proteins of severe acute respiratory syndrome coronavirus and human coronavirus NL63
Patient representatives' contributions to the benefit-risk assessment tasks of the European Medicines Agency scientific committees
An interaction of renin-angiotensin and kallikrein-kinin systems contributes to vascular hypertrophy in angiotensin II-induced hypertension: in vivo and in vitro studies
Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg9 bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration
Bifunctional ligands of the bradykinin B2 and B1 receptors: An exercise in peptide hormone plasticity
Understanding SARS-CoV-2-Mediated Inflammatory Responses: From Mechanisms to Potential Therapeutic Tools.
Reply to Siniorakis et al., "COVID-19 Interference with Renin-Angiotensin System in the Context of Heart Failure"
The renin-angiotensin-aldosterone system: Role in pathogenesis and potential therapeutic target in COVID-19.
Pathogenesis and Treatment Strategies of COVID-19-Related Hypercoagulant and Thrombotic Complications
Coagulation Abnormalities and Thrombosis in Patients Infected With SARS-CoV-2 and Other Pandemic Viruses.
Anticoagulation use and Hemorrhagic Stroke in SARS-CoV-2 Patients Treated at a New York Healthcare System.
Inhibiting fusion with cellular membrane system: therapeutic options to prevent severe acute respiratory syndrome coronavirus-2 infection.
COVID's Razor: RAS Imbalance, the Common Denominator Across Disparate, Unexpected Aspects of COVID-19
A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm.
Immunomodulatory Therapeutic Proteins in COVID-19: Current Clinical Development and Clinical Pharmacology Considerations
Review of influenza-associated pulmonary aspergillosis in ICU patients and proposal for a case definition: an expert opinion
A systematic review of pathological findings in COVID-19: a pathophysiological timeline and possible mechanisms of disease progression.
The Controversy of Renin-Angiotensin-System Blocker Facilitation Versus Countering COVID-19 Infection.
Impaired Breakdown of Bradykinin and Its Metabolites as a Possible Cause for Pulmonary Edema in COVID-19 Infection
Interferons and viruses induce a novel truncated ACE2 isoform and not the full-length SARS-CoV-2 receptor.
Renin-Angiotensin System: An Important Player in the Pathogenesis of Acute Respiratory Distress Syndrome
Angiotensin-converting enzyme 2, the complement system, the kallikrein-kinin system, type-2 diabetes, interleukin-6, and their interactions regarding the complex COVID-19 pathophysiological crossroads
Sensitive mass spectrometric determination of kinin-kallikrein system peptides in light of COVID-19.
Emerging Mechanisms of Pulmonary Vasoconstriction in SARS-CoV-2-Induced Acute Respiratory Distress Syndrome (ARDS) and Potential Therapeutic Targets.
Clinical Trials Mentioned
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