Mechanisms of CSS in COVID-19
The cytokine storm in COVID-19 may vary from the cytokine storms in other clinical settings. It was revealed by autopsy findings, that the lymphoid tissues were destroyed in COVID-19 patients, which is rare from CSS in sepsis and CAR T-cell therapy. Spleen and lymph node atrophy are observed in patients with COVID-19, while lymphadenopathy and splenomegaly are more common in other CSS-related diseases. However, the specific mechanisms for these differences remain unclear and need to be further studied [9].
Coronaviruses (CoVs) are enveloped single-stranded RNA viruses, which have caused two marked pandemics SARS and MERS [9]. Spike (S) proteins of coronaviruses, including the SARS-CoV, facilitate entry into their target cells via the interaction with angiotensin-converting enzyme 2 (ACE2), a functional cellular receptor, which is highly expressed in vascular endothelial cells, alveolar epithelial cells, intestinal epithelial cells and renal proximal tubular cells. ACE2 suppresses angiotensin Ⅱ(AngⅡ) and activates the formation of angiotensin 1–7, a which is a vasodilator heptapeptide. The binding of the coronavirus spike protein to ACE2 leads to the down-regulation of ACE2, which in turn results in excessive production of vasoconstrictor AngⅡ and reduced production of vasodilator angiotensin 1–7.
Furthermore, AngⅡ binds to the angiotensin receptor 1 (AT1R) and plays a role of proinflammatory cytokine. The AngⅡ-AT1R axis activates NF-κB and metalloprotease 17 (ADAM17), which stimulates the production of the epidermal growth factor receptor (EGFR) ligands and TNF-α, which activate the IL-6 amplifier (IL-6 Amp), and lead to a hyperinflammatory status, resulting in increased vascular permeability of the lungs [10].
A retrospective study also found higher plasma concentrations of IL-2, IL-7, IL-10, IP-10, MCP-1, and TNF-α in intensive care unit (ICU) patients compared with nonsevere patients, suggesting a cytokine storm in severe patients [11].