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Review
. 2022 Nov 1:128:72-102.
doi: 10.1016/j.niox.2022.08.003. Epub 2022 Aug 24.

Utility of NO and H2S donating platforms in managing COVID-19: Rationale and promise

Palak P Oza  1 , Khosrow Kashfi  2
Affiliations
Review

Utility of NO and H2S donating platforms in managing COVID-19: Rationale and promise

Palak P Oza et al. Nitric Oxide. .

Abstract

Viral infections are a continuing global burden on the human population, underscored by the ramifications of the COVID-19 pandemic. Current treatment options and supportive therapies for many viral infections are relatively limited, indicating a need for alternative therapeutic approaches. Virus-induced damage occurs through direct infection of host cells and inflammation-related changes. Severe cases of certain viral infections, including COVID-19, can lead to a hyperinflammatory response termed cytokine storm, resulting in extensive endothelial damage, thrombosis, respiratory failure, and death. Therapies targeting these complications are crucial in addition to antiviral therapies. Nitric oxide and hydrogen sulfide are two endogenous gasotransmitters that have emerged as key signaling molecules with a broad range of antiviral actions in addition to having anti-inflammatory properties and protective functions in the vasculature and respiratory system. The enhancement of endogenous nitric oxide and hydrogen sulfide levels thus holds promise for managing both early-stage and later-stage viral infections, including SARS-CoV-2. Using SARS-CoV-2 as a model for similar viral infections, here we explore the current evidence regarding nitric oxide and hydrogen sulfide's use to limit viral infection, resolve inflammation, and reduce vascular and pulmonary damage.

Keywords: Antiviral; COVID-19; Cytokine storm; Endothelium; Hydrogen sulfide; Inflammation; Nitric oxide; iNOS.

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Conflict of interest statement

Declaration of competing interest The authors declare no conflict of interest.

Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
SARS-CoV-2 entry into the host cell. As an enveloped virus, SARS-CoV-2 can enter the host cell through one of two pathways - pathway #1, endosomal entry and pathway #2, direct cell surface entry. In both entry forms, the S protein binds to the ACE2 receptor and must be primed and activated by proteases at the S1/S2 and S2’ site. SARS-CoV-2 infection results in the downregulation of the ACE2 receptor, leading to an increase in Ang II and decrease in its conversion to Ang 1–7. In pathway #1, SARS-CoV-2 undergoes clathrin-mediated endocytosis, and is primed by host protease Cathepsin L present in the endolysosome, followed by membrane fusion and release of viral genomic material. In pathway #2, the S protein is cleaved by TMPRSS2 at the cell membrane, where it directly fuses and releases viral RNA without entering an endolysosome. Both pathways join in the host cytoplasm, where a viral polymerase is translated, followed by RNA replication, structural protein translation, viral assembly, and release of progeny virus that continue to spread the infection to other cells. SARS-CoV-2 infection leads to respiratory compromise by causing lung injury, results in excessive inflammation with overactivation of leukocytes and production of inflammatory mediators, results in direct and inflammation-mediated damage to the endothelium, and induces a pro-thrombotic state. Abbreviations: ACE2, angiotensin converting enzyme 2; Ang, angiotensin; S protein, spike protein; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TMPRSS2, transmembrane serine protease 2.
Fig. 2
Fig. 2
Cytokine storm in COVID-19. Cytokine storm is characteristic of severe COVID-19 cases and results in lung injury, endothelial damage and thrombosis, and multi-organ damage that can lead to death. The following steps are responsible for the hyperinflammatory response that occurs in COVID-19: 1) SARS-CoV-2 enters the lung and infects the lung cells. These cells recognize PAMPS from the virus and begin pro-inflammatory gene transcription using transcription factors such as IRFs and NFκB, resulting in the release of pro-inflammatory cytokines and other mediators, which are recognized by leukocytes. 2) PAMPs and DAMPs are recognized by tissue macrophages, which become activated and secrete more pro-inflammatory cytokines to recruit and activate other leukocytes to the site of infection, including T lymphocytes, NK cells, neutrophils, and more monocytes to enter through the blood and differentiate into macrophages. 3) Together, these activated cells produce excess cytokines and chemokines, including IL-1β, IL-6, TNF-α, among others, that continue the cycle, diffusing into the blood and recruiting even more leukocytes. Microbial killing by these activated leukocytes involves neutrophil production of ROS as well as T cell mediated cytotoxicity, leading to inflammatory damage to the tissue, lymphocyte exhaustion, excessive neutrophil infiltration. In the vasculature, the endothelium undergoes activation, causing a shift to a pro-inflammatory, prothrombotic state which can facilitate thrombus formation and leukocyte migration into the infected tissue. 4) Fibrin deposition in the air spaces exacerbates the damage. 5) Inflammation leads to increased gaps between endothelial cells, resulting in vascular leakage and edema in the air spaces, leading to respiratory failure. Abbreviations: COVID-19, coronavirus disease 2019; DAMPs, damage associated molecular patterns; IL, interleukin; IRF, interferon regulatory factors; NFκB, nuclear factor kappa light chain enhancer of activated B cells; NK, natural killer; PAMPs, pathogen associated molecular patterns; ROS, reactive oxygen species; SARS-CoV-2, severe acute respiratory syndrome; TNF, tumor necrosis factor.
Fig. 3
Fig. 3
Role of NO in COVID-19. Previous studies with SARS-CoV-1 suggest that NO may inhibit viral entry of SARS-CoV-2 by disrupting post-translational palmitoylation of the S protein, and studies conducted with SARS-CoV-2 demonstrate that NO inhibits viral replication by inhibiting SAS-CoV-2 3CL protease that is necessary for replication. NO increases mucociliary clearance by increasing ciliary beat frequency as well as mucus secretion, acting as a first line of host defense against airborne pathogens in the respiratory tract. During later stages of infection, NO plays a role in resolving inflammation - NO inhibits the expression of adhesion molecules in the endothelium thus inhibiting leukocyte adhesion and transmigration, promotes macrophage switching from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype, upregulates the release of anti-inflammatory cytokines while suppressing pro-inflammatory cytokines, and exerts feedback inhibition on iNOS to curtail excess NO production that can occur in hyperinflammation. Within the vasculature, NO induces vasorelaxation through cGMP-mediated signaling and reduces platelet aggregation and thrombus formation. Within the lungs, NO improves ventilation and perfusion through broncho- and pulmonary vaso-dilation, respectively, and limits the need for MV, thereby reducing the occurrence of lung injury from MV. The antimicrobial actions of NO are also important in preventing secondary infections, and application of NO donors has been shown to reduce bacterial adhesion to biomedical devices, an important application where MV, ECMO, and other invasive support is needed. Abbreviations: cGMP, cyclic guanosine monophosphate; ECMO, extracorporeal membrane oxygenation; iNOS, inducible nitric oxide synthase; M1, classically activated macrophage; M2, alternatively activated macrophage; MV, mechanical ventilation; NO, nitric oxide; S protein, spike protein; SARS-CoV-1, severe acute respiratory syndrome 1; SARS-CoV-2, severe acute respiratory syndrome 2.
Fig. 4
Fig. 4
Role of H2S in COVID-19. H2S inhibits viral entry by downregulating host TMPRSS2 which prevents S protein activation, and may prevent binding to the ACE2 receptor through disruption of ACE2 disulfide bonds. Additionally, H2S inhibits genome and protein replication, assembly, and release of several viruses likely including SARS-CoV-2. H2S increases mucociliary clearance as a host defense against respiratory pathogens by reducing mucus viscosity and increasing mucus hydration, by breaking mucin disulfide bonds and inhibiting Na+ reabsorption through epithelial Na+ channels, respectively. During later stages of infection, H2S serves a protective role by inhibiting pro-inflammatory transcription factor NFκB, reducing the release of proinflammatory cytokines while increasing anti-inflammatory cytokines and promoting inflammation resolution. H2S inhibits iNOS while upregulating eNOS, and inhibits leukocyte adhesion and transmigration. In the endothelium, in addition to increasing eNOS function, H2S also inhibits PDE5, increasing NO bioavailability and its anti-inflammatory, anti-thrombotic, and vasorelaxant effects. H2S directly induces vasorelaxation through K+ channel stimulation and exerts anti-thrombotic effects. In the lungs, H2S reduces apoptosis, improves ventilation and perfusion through broncho- and pulmonary vaso-dilation, respectively, protects against Ang II-induced lung injury by upregulating ACE2, and reduces the need for MV, reducing MV-related lung injury. H2S also upregulates antioxidant machinery including GSH and SOD, directly scavenges peroxynitrite and ROS, and inhibits iNOS and the production of ROS. Abbreviations: ACE2, angiotensin converting enzyme 2; Ang II, angiotensin II; eNOS, endothelial nitric oxide synthase; GSH, glutathione; H2S, hydrogen sulfide; iNOS, inducible nitric oxide synthase; K+, potassium ion; MV, mechanical ventilation; Na+, sodium ion; NFκB, nuclear factor kappa light chain enhancer of activated B cells; NO, nitric oxide; PDE5, phosphodiesterase 5; ROS, reactive oxygen species; S protein, spike protein; SARS-CoV-2, severe acute respiratory syndrome 2; SOD, superoxide dismutase; TMPRSS2, transmembrane serine protease 2.
Fig. 5
Fig. 5
NO and H2S crosstalk. NO, and H2S interact at multiple levels to mutually impact production and downstream signaling and create new reaction products. NO – enzymatically produced from l-arginine by nNOS, eNOS, and iNOS mediates most of its downstream effects through the sGC-cGMP pathway. Superoxide reduces NO production by causing NOS uncoupling and consumes NO to form peroxynitrite. NO signaling is terminated by PDE5A, which degrades cGMP. H2S is produced enzymatically by CBS, CSE, and 3-MST in conjunction with CAT. NO upregulates CSE expression and, in a cell-free system, inhibits CBS activity. H2S has a dual effect on eNOS activity and expression that may be dependent on the release kinetics of donor molecules, concentration, and other factors; it may either inhibit eNOS or increase eNOS activity via intracellular Ca2+ release or Akt-mediated phosphorylation. Similar biphasic effects are noted upon NF-κB, the transcription factor for iNOS. H2S also reduces superoxide production, thereby reducing NO consumption to produce peroxynitrite; additionally, H2S is a scavenger of peroxynitrite as well. H2S augments downstream signaling of NO by increasing sGC activity and inhibiting PDE5A. NO and H2S may also combine to form new species such as RSNO, HNO, and HSNO, which produce different effects than either gasotransmitter alone. Abbreviations: 3-MST, 3-mercaptopyruvate sulfurtransferase; Ca2+, calcium ion; CAT, cysteine aminotransferase; CBS, cystathionine β-synthase; cGMP, cyclic guanosine monophosphate; CSE, cystathionine γ-lyase; eNOS, endothelial nitric oxide synthase; H2S, hydrogen sulfide; HNO, nitroxyl; HSNO, thionitrous acid; iNOS, inducible nitric oxide synthase; NF-κB, nuclear factor kappa light chain enhancer of activated B cells; nNOS, neuronal nitric oxide synthase; NO, nitric oxide; PDE5A, phosphodiesterase type 5A; RSNO, nitrosothiol; sGC, soluble guanylyl cyclase; RSNO, nitrosothiol; HSNO, thionitrous acid; H2Sn, polysulfide; HNO, nitroxyl; ONSS−, nitropersulfide.
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