Figure 2.
Multiple organ failure in SARS-CoV-2: pulmonary and extrapulmonary manifestations. Pulmonary manifestations: (A) Alveolar cells are infected by the angiotensin-converting enzyme 2 (ACE2) receptor. This leads to acute lung injury (ALI), activation of the renin-angiotensin system (RAS), and macrophage recruitment. Macrophages, activated by the ACE2-Ang II axis, can secrete IL-6, CCL2, VCAM-1, and E-selectin leading to endothelial dysfunction. Damaged endothelial cells may cause hyperfibrinolysis, activate coagulation, and increase inflammatory cytokine levels (IL-1 and TNF), which are strong inducers of hyaluronic acid-synthase-2 (HAS2) in CD31+ endothelium, EpCAM+ lung alveolar epithelial cells, and fibroblasts. The increased hyaluronic acid may cause bronchoconstriction. Extrapulmonary manifestations: (B) In neurons, elevated TNF-α and IL-6 secretions could increase the infiltration of immune cells and the permeability of the blood and cerebrospinal fluid barrier (BCSFB). CX3CL1 could also promote neurological vascular damage and thrombosis. IL-6 along with GM-CSF, IL-1β, TNF-α, CCL2, and CXCL10, could increase the severity of neurodegeneration, cognitive dysfunction, and stroke. (C) In the heart, infected cardiomyocytes would induce elevated secretions of IL-1, IL-6, TNF-α, and CCL2, damaging the myocardium and developing into hypoxia, respiratory distress, and even shock. (D) In the kidney, SARS-CoV-2 infects ACE2 expressing proximal tubules and the podocytes. The infected podocytes promote an imbalanced RAS, which leads to acute kidney injury (AKI). Moreover, IL-6, IL-1β, IL-10, GM-CSF, IFNs, CXCL10, CCL2 and TNF-α promote AKI persistence. (E) In the liver, infected hepatocytes trigger elevated serum IL-1, IL-2, IL-6, IL-10, and IFNγ, as well as pathogenic cytokine secretions mediated by T cells (GM-CSF, IL-6, and IFN-γ). The immune-mediated injury would lead to liver dysfunction and systemic inflammatory response syndrome (SIRS). Figure created with BioRender.com.