Figure 1.

ACE2 is present in the alveolar epithelium and is the receptor for SARS–CoV-2 via the spike protein.³ Following binding, there is decreased availability of ACE2 and therefore decreased activity. This downregulation of ACE2 by COVID-19 results in increases in the substrates of ACE2, AngII and BK.⁶ COVID-19 infection also shows evidence of an increase in HA synthase 2 expression which will upregulate the production of HA and can lead to fluid retention and decreased gas permeability and acute respiratory distress syndrome often seen in COVID-19 patients.^6,8 In response to the infection, the pro-inflammatory cytokine, IL-6, is upregulated. This overexpression of IL-6 indirectly causes an increase in B1Rs on the cell surface and also indirectly causes the downregulation of SERPINA12, a suppressor for bradykinin, subsequently increasing the cell’s affinity for the uninhibited bradykinin. Abbreviations: ACE2, angiotensin-converting enzyme 2; Ang II, angiotensin II; AT₁R, angiotensin II receptor type 1; AT₂R, angiotensin II receptor type 2; BK, bradykinin; B₁R, bradykinin-1 receptor; B₂R, bradykinin-2 receptor; COVID-19, coronavirus disease 2019; HA, hyaluronic acid; HMW, high molecular weight; IL-6, interleukin-6; SARS–CoV-2, severe acute respiratory syndrome of coronavirus 2; SERPINA12, serpin family A member 12.^1,2