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Review
. 2021 Nov 11:12:749291.
doi: 10.3389/fimmu.2021.749291. eCollection 2021.

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

Hayder M Al-Kuraishy  1 , Ali Ismail Al-Gareeb  1 , Gomaa Mostafa-Hedeab  2 , Keneth Iceland Kasozi  3   4 , Gerald Zirintunda  5 , Akhmed Aslam  6 , Mamdouh Allahyani  7 , Susan Christina Welburn  3   8 , Gaber El-Saber Batiha  9
Affiliations
Review

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

Hayder M Al-Kuraishy et al. Front Immunol. .

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a causative virus in the development of coronavirus disease 2019 (Covid-19) pandemic. Respiratory manifestations of SARS-CoV-2 infection such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) leads to hypoxia, oxidative stress, and sympatho-activation and in severe cases leads to sympathetic storm (SS). On the other hand, an exaggerated immune response to the SARS-CoV-2 invasion may lead to uncontrolled release of pro-inflammatory cytokine development of cytokine storm (CS). In Covid-19, there are interactive interactions between CS and SS in the development of multi-organ failure (MOF). Interestingly, cutting the bridge between CS and SS by anti-inflammatory and anti-adrenergic agents may mitigate complications that are induced by SARS-CoV-2 infection in severely affected Covid-19 patients. The potential mechanisms of SS in Covid-19 are through different pathways such as hypoxia, which activate the central sympathetic center through carotid bodies chemosensory input and induced pro-inflammatory cytokines, which cross the blood-brain barrier and activation of the sympathetic center. β2-receptors signaling pathway play a crucial role in the production of pro-inflammatory cytokines, macrophage activation, and B-cells for the production of antibodies with inflammation exacerbation. β-blockers have anti-inflammatory effects through reduction release of pro-inflammatory cytokines with inhibition of NF-κB. In conclusion, β-blockers interrupt this interaction through inhibition of several mediators of CS and SS with prevention development of neural-cytokine loop in SARS-CoV-2 infection. Evidence from this study triggers an idea for future prospective studies to confirm the potential role of β-blockers in the management of Covid-19.

Keywords: Beta blockers; SARS-CoV-2; cytokine storm; pharmacology and Covid; sympathetic storm.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
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.
Figure 2
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.
Figure 3
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.
Figure 4
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.
Figure 5
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.
Figure 6
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.
Figure 7
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.
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