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Fig. 1 | Critical Care

Fig. 1

From: The vascular endothelium: the cornerstone of organ dysfunction in severe SARS-CoV-2 infection

Fig. 1

The role of endothelial cells in SARS-CoV-2 infection and treatment. a Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds with Angiotensin- converting enzyme 2 (ACE2) on the cell membrane of the host cells. Cell invasion also depends on the presence of the protease Transmembrane protease serine 2 (TMPRSS-2) that is able to cleave the viral spike. The recombinant protein of human ACE2 fused with the Fc region of the human immunoglobulin IgG1 (rACE2-IgG1) binds with high affinity to the receptor-binding domain of SARS-CoV-2. Moreover, a protease TMPRSS2 inhibitor is efficient to block SARS-CoV-2 entry into the endothelial cells (ECs). b In patients diagnosed with severe COVID-19, increased levels of pro-inflammatory cytokines, in particular, the soluble interleukin 2-receptor (IL-2R) and interleukin-6 (IL-6) have been observed. ECs express both IL-6 receptor (IL-6R) and IL-2R on their surface. Soluble IL-2R (sIL-2R) is mostly secreted by activated T helper lymphocytes, but might be also secreted by ECs. Binding of IL-6 and IL-2 on their receptors induces a capillary leak. Moreover, IL-6 signaling induces the secretion by ECs of more IL-6 and other cytokines. Tocilizumab, a humanized anti-IL-6 receptor (IL-6R) antibody that inhibits signal transduction by binding sIL-6R and membrane-bound IL-6R, has emerged as a potential immunomodulatory treatment in COVID-19 patients. c During SARS-CoV-2 infection, endothelial dysfunction and microthrombi formation may be secondary to complement activation and membrane attack complexes deposits on ECs. Eculizumab, a human monoclonal antibody designed to bind to the complement protein C5 with high affinity prevents the generation of the terminal membrane attack complex. EC activation also induces a pro-coagulant state by increasing their production of von Willebrand factor (vWF) and factor VIII (FVIII), which participate in clot formation. Heparin from prophylactic to therapeutic doses has been used in COVID-19 patients to inhibit clot formation. Moreover, during SARS-CoV-2 infection, ECs increase their production of plasminogen activator inhibitor 1 (PAI-1), which inhibits the conversion of plasminogen to plasmin and the degradation of clots inducing a hypofibrinolytic state. Tissue plasminogen activator (t-PA) has been tested in COVID-19 patients for its fibrinolytic effect. ACE2: angiotensin-converting enzyme 2; C5: complement C5; FVIII: factor VIII; FDP: fibrin degradation product; IL-2: interleukin-2; IL-6: interleukin-6; IL-2R: interleukin-2 receptor; IL-6-R: interleukin-6 receptor; MAC: membrane attack complex; PAI 1: plasminogen activator inhibitor 1; rACE2-IgG1: recombinant angiotensin-converting enzyme 2 immunoglobulin G1; SARS-Cov-2: severe acute respiratory syndrome coronavirus 2; sIL-2R: soluble interleukin 2 receptor, sIL-6R: soluble interleukin 6 receptor; Th L: T helper lymphocyte; TMPRSS-2: transmembrane protease serine 2 t-PA: tissue plasminogen activator; vWF: von Willebrand factor

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