Effects of β-Blockers on the Sympathetic and Cytokines Storms in Covid-19

Figures

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  Figure 1. SARS-CoV-2 infection and development of sympathetic and cytokine storms: Central effect of SARS-CoV-2 leads to brain injury and development of sympathetic storm (SS). The peripheral effect of SARS-CoV-2 leads to induction imbalance between the sympathetic nervous system (SNS) and parasympathetic nervous system (PSNS) and development of cytokine storm (CS). Both SS and CS lead to Covid-19 severity.

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  Figure 2. SARS-CoV-2-induced sympathetic storm. SARS-CoV-2 acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)-induced hypoxia, SARS-CoV-2-induced neuroinflammation, and release of pro-inflammatory cytokines activate the central sympathetic center with the development of the sympathetic storm.

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  Figure 3. SARS-CoV-2 and release of pro-inflammatory cytokines: SARS-CoV-2 activates the sympathetic center, increases activity of the sympathetic nervous system (SNS), the release of catecholamine, which activates the expression of CD147 that increase viral entry. SARS-CoV-2 downregulates ACE2 which increases circulating angiotensin II (AngII). SARS-CoV-2 inhibits anti-inflammatory nicotinic acetylcholine receptor (nAChR) with reduced activity of the parasympathetic nervous system (PSNS). These changes together trigger the release of pro-inflammatory cytokines.

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  Figure 4. Role of β-blockers in lung protection: β-blockers inhibit sympathetic nervous system (SNS), renin release, locus coeruleus (LC) activity, and central presynaptic β2 receptors that decrease the release of catecholamine and angiotensin II (AngII) with subsequent inhibition of sympathetic storm and lung protection.

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  Figure 5. Role of SARS-CoV-2 in the development of cytokine storm (CS): SARS-CoV-2 through activation of CD147 activate myeloid differentiation 88 (MyD88), through toll-like receptor 4 (TLR4) and ACE2 activate angiotensin II (AngII) that together trigger NF-κB pathway, which stimulates the release of pro-inflammatory pathway and development of cytokine storm.

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  Figure 6. Catecholamine and acute lung injury: catecholamine during SARS-CoV-2-induced sympathetic storm, activates β1, which activates NF-κB and NLRP3 inflammasome of immune cells macrophages and neutrophils induces the release of pro-inflammatory cytokines. Activation of immune cells triggers the generation of reactive oxygen species (ROS), activation of β2 leads to the development of endothelial dysfunction, coagulopathy, and thrombosis. Together these changes cause acute lung injury (ALI) and acute respiratory syndrome (ARDS). Inhibitory effects of β-blockers.

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  Figure 7. Role of β-blockers in the irruptions of the crosstalk between cytokine (CS) and sympathetic storms(SS): β-blockers block reduces the release of catecholamine and decreases its stimulatory effect on β2, CD147, and immune cells with reduction release of pro-inflammatory cytokines. The anti-inflammatory effects of β-blockers also attenuate CS-induced acute lung injury (ALI) and acute respiratory syndrome (ARDS), development of oxidative stress (OS), and final systemic complications.