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.
Highlights
COVID-19 infects mainly elderly and people with cardiovascular risk, such as hypertension (Guan et al, 2020)
Every clinician recognizes that the virus does not cause disease similar to influenza, which carries the risk that designing targeted therapies based on the pathogenesis of influenza might fail in COVID-19
Research on Sars-CoV pathogenesis which might be very similar to Sars-CoV-2 pathogenesis has focused the discussion on ACE inhibitors, recombinant ACE2, and ARBs and how they could fit in the pathogenesis of COVID-19, since these pathways were extensively studied in SARS (Fang et al, 2020; Batlle et al, 2020)
Summary
COVID-19 infects mainly elderly and people with cardiovascular risk, such as hypertension (Guan et al, 2020). This led van de Veerdonk et al to propose that the excess of fluid in the lungs seen in COVID-19 patients may be because kinins are not being neutralized due to the shortage of the ACE2 receptor This had not been hypothesized before, even though the mechanism could be the same in SARS which has been researched for the past 17 years. If this hypothesis is correct, it would mean that directly inhibiting the receptor for the kinins (or the proteins that they come from) may be the only way to stop fluid leaking into the lungs of COVID-19 patients in the early stage of disease. We and others have suggested that the L-type may progress to the H-type by a combination of negative intrathoracic pressure and increased lung permeability due to inflammation (so called patientself inflicted lung injury P-SILI) (Gattinoni et al, 2020b)
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