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Table of Contents
Year : 2021  |  Volume : 64  |  Issue : 4  |  Page : 167-176

Participation of nitrogen oxide and its metabolites in the genesis of hyperimmune inflammation in COVID-19

1 Department of Pathomorphology and Clinical Pathophysiology, Medical Institute, FSBEI HE “Maikop State Technological University”, Maikop, Republic of Adygeya, Russia
2 Immunogenetic Laboratory of the Research, Institute of Complex Problems, FSBEI HE “Adyghe State University”, Maikop, Republic of Adygeya, Russia

Date of Submission20-May-2021
Date of Decision26-Jul-2021
Date of Acceptance09-Aug-2021
Date of Web Publication28-Aug-2021

Correspondence Address:
Dmitriy Sergeevich Shumilov
Department of Pathomorphology and Clinical Pathophysiology, Medical Institute, FSBEI HE “Maikop State Technological University”, Maikop, Republic of Adygeya, 385000
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/cjp.cjp_38_21

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Despite the success in the tactics of treating COVID-19, there are many unexplored issues related to the development and progression of the process in the lungs, brain, and other organs, as well as the role of individual elements, in particular, nitric oxide (NO), and in the pathogenesis of organ damage. Based on the analyzed literature data, we considered a possible pathophysiological mechanism of action of NO and its derivatives in COVID-19. It can be noted that hyperimmune systemic inflammation and “cytokine storm” are enhanced by the production of NO, products of its oxidation (“nitrosative stress”). It is noted in the work that as a result of the oxidation of NO, a large amount of the toxic compound peroxynitrite is formed, which is a powerful proinflammatory agent. Its presence significantly damages the endothelium of the vascular walls and also oxidizes lipids, hemoglobin, myoglobin, and cytochrome, binds SH-groups of proteins, and damages DNA in the target cells. This is confirmed by the picture of the vessels of the lungs on computed tomography and the data of biochemical studies. In case of peroxynitrite overproduction, inhibition of the synthesis of NO and its metabolic products seems to be justified. Another aspect considered in this work is the mechanism of damage by the virus to the central and peripheral nervous system, which remains poorly understood but may be important in understanding the consequences, as well as predicting brain functions in persons who have undergone COVID-19. According to the analyzed literature, it can be concluded that brain damage is possible due to the direct effect of the virus on the peripheral nerves and central structures, and indirectly through the effect on the endothelium of cerebral vessels. Disturbances in the central nervous regulation of immune responses may be associated with the insufficient function of the acetylcholine anti-inflammatory system. It is proposed to further study several approaches to influence various links of NO exchange, which are of interest for theoretical and practical medicine.

Keywords: Brain, COVID-19, lungs, nitric oxide, peroxynitrite, vascular endothelium

How to cite this article:
Lysenkov SP, Muzhenya DV, Tuguz AR, Urakova TU, Shumilov DS, Thakushinov IA. Participation of nitrogen oxide and its metabolites in the genesis of hyperimmune inflammation in COVID-19. Chin J Physiol 2021;64:167-76

How to cite this URL:
Lysenkov SP, Muzhenya DV, Tuguz AR, Urakova TU, Shumilov DS, Thakushinov IA. Participation of nitrogen oxide and its metabolites in the genesis of hyperimmune inflammation in COVID-19. Chin J Physiol [serial online] 2021 [cited 2023 Dec 4];64:167-76. Available from: https://www.cjphysiology.org/text.asp?2021/64/4/167/324870

FSBEI HE - Federal State Budget Educational Institution of Higher Education

  Introduction Top

The global pandemic COVID-19 poses complex and multifaceted tasks for scientists of different profiles, the solution of which is aimed at understanding the mechanisms of virus infiltration into the body, pathophysiological and pathomorphological manifestations, as well as possible consequences after a disease. Therefore, the publication of practical results, theoretical proposals, and hypotheses is a very important step for the formation of a holistic understanding of the treatment and prevention of the disease.

According to the published results, one of the main routes of entry of the virus into the body is through interaction with the ACE2 and SRB1 receptors. It was found that using spikes, the virus contacts the ACE2 receptor and attaches to the cell, as well as through the SRB1 receptor attaches to the cholesterol molecule. Another possible viral invasion mechanism could be the synergy of SARS-CoV-2 with the human serine protease serine-2 (TMPRSS2). Viral glycoprotein S is cleaved by TMPRSS2, thus facilitating its activation and further penetration into the body. It should be noted that during the development of the disease, the hyperimmune response of the body is a feature of the immune response.[1],[2],[3],[4],[5]

By damaging various types of cells (alveocytes, macrophages, T-cells, etc.), the virus causes a huge release of proinflammatory cytokines, the so-called “cytokine storm.” The occurrence of this effect inactivates the synthesis of all forms of nitric oxide synthases (NOSs) inducing the production of large amounts of nitric oxide (NO), which acts as one of the key mediators of local inflammation.[6],[7],[8]

It is known today that, under physiological conditions, NO is involved in immune defense, providing a cytotoxic effect, in synaptic transmission of nerve impulses and long-term memory consolidation, intestinal motility, and many other physiological processes.[9],[10],[11],[12] NO synthesis is carried out under the action of the NOS enzyme in the cells, as a rule, having an ACE2 receptor: epithelial, endotheliocytes, macrophages, neutrophils, mast cells, and T-lymphocytes. Endothelial nitric oxide synthase (eNOS) is in the endothelium of organs, neuronal nitric oxide synthase (nNOS) is in the heart muscle and neurons, and inducible nitric oxide synthase (iNOS) is in macrophages and tissues. Calcium (calmodulin) is required for the activation of eNOS and nNOS, while calcium is not required for iNOS. Activation of iNOS was noted under the action of interleukin-1β, interferon-γ, tumor necrosis factor-α, lipopolysaccharides of Gram-negative bacteria, etc.[10],[11]

  The Role of Nitric Oxide and Its Compounds Top

It is known that physiological concentrations of NO (5–10 nmol) have vasodilatory, bronchodilatory, antiapoptotic, antiplatelet, antioxidant, and antiproliferative effects. Cyclic guanylate cyclase is expressed in the smooth muscle cells of the respiratory tract most actively under the action of NO, providing a bronchodilator effect. After synthesis, it diffuses inside the surrounding tissue, including inside the smooth muscle cells of the vessels adjacent to the alveoli. NO provides vasodilation, well-ventilated alveoli, ensuring the functioning of the Euler-Liljestrand reflex.[13],[14] Perhaps, this explains the lack of growth of the lung resistance and decreased elasticity of lung tissue in mild to moderate-severe COVID pneumonia.

It should be noted that NO mediates signal transmission from cytokines, contributing to the normal function of innate immunity.[15],[16] For example, the balance of Th1 and Th2 determines the direction of the immunological response either by inhibition of iNOS/NO activity (with an increase in Th2 lymphocyte activity) or by stimulation of iNOS/NO production (with prevalence of Th1 activity).[16] NO is also able to enhance the production of tumor necrosis factor (TNF)-gamma by natural killer (NK) cells, increasing their cytolytic activity. However, excessive production of NO impairs the function of NK cells, which occurs when the body is heavily infected.[17],[18] Therefore, the direction of the reactions of the formation of NO and its derivatives depends on the “amount” or “dose” of the viruses that enter the body.

There is evidence that increased concentrations of NO and its derivatives can inhibit DNA synthesis, inactivate iron-sulfur proteins by S-nitrosylation, and inhibit glycolysis, thereby disrupting cell metabolism.[19],[20],[21]

On the other hand, high concentrations of NO can damage the endothelium and provoke a tendency to thrombus formation and impairment of microcirculation in target organs and, first of all, in the lungs [Figure 1]. As a result, “nitrosative stress” is observed, which, together with oxidative stress, aggravates the course of the “cytokine storm.”[22],[23],[24],[25],[26],[27]
Figure 1: Activation of the synthesis of nitric oxide and peroxynitrite (its derivatives) during infection with the COVID-19 virus. NDX: Nucleus dorsalis n. vagi; IFN-γ, IL-1, TNF-α, IL-6, inflammatory mediators (proinflammatory cytokines) of the first wave; ×: Track block; ↑: Increase; ↓: Decrease.

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  Peroxynitrite and Its Pathological Role Top

It should be noted that with reactive oxygen species, NO forms an extremely toxic product – peroxynitrite. The interaction of NO and O2 is accompanied by the formation of the anion of peroxynitrate (OONOO, the product of nitrous anhydride N2O3) and peroxynitrite (ONOO). The peroxynitrite anion dissociates into nitrate anion (NO2) and oxygen O2, and N2O3 forms nitrosothiols with thiol (SH) groups. In turn, a reaction between the products of NO exchange is possible: dinitrogen trioxide reacts with peroxynitrite, forming two molecules of nitrogen dioxide and one molecule of NO2.[28],[29],[30] That is the reaction, which predominantly takes place during inflammation and excessive synthesis of NO since the formation of peroxynitrite during inflammatory processes increases 1,000,000 times and the superoxide anion radical increases only 1,000 times.[31]

In addition, peroxynitrite, combining with carbon dioxide (CO2), forms nitrosoperoxycarbonate, which decomposes very quickly into NO2 and the strongest oxidizing agent – CO3.[32] Interestingly, many of the physiological effects of NO are due to peroxynitrite. At the same time, peroxynitrite is the most aggressive endogenous compound, causing a whole range of pathological effects. In addition, the superoxide radical O2 is formed during the autoxidation of oxyhemoglobin, which, in turn, together with NO, forms peroxynitrite (ONOO). Combining with a hydrogen ion, peroxynitrite forms another toxic compound – peroxynitrous acid (HOONO). However, in the human body, the reactions of the formation of carbonate radicals prevail to a greater extent, since the concentration of CO2 is 10,000 times more than hydrogen ions. Peroxynitrite in combination with CO2 forms unstable nitrosoperoxycarbonate (ONOOCO2). This compound decomposes and turns into nitrocarbonate (O2NOCO2). Further, 96% ± 1% of nitrate is formed from this compound and only 3 ± 1% NO2* and CO3*. These reactions are considered to be the main ones in biological systems.[33],[34]

Peroxynitrite oxidizes lipids, hemoglobin, myoglobin, cytochrome, and DNA in the target cells: all blood cells and mitochondria bind SH-groups of proteins.[35],[36] It also paracrinely damages the endothelium, the basement membrane of blood vessels, activates adhesion molecules, causing a systemic inflammatory process, and activating the coagulation system, including first vascular platelet and coagulation hemostasis. In the lungs, this is manifested by microthrombosis, vasodilation, infiltration by macrophages and neutrophils of individual vascular zones, edema of the intercellular and interstitial space, and desquamation of the epithelium and endothelium.[37],[38],[39] A similar picture is observed in other organs: intestines, heart, kidneys, and liver. Hence, for example, “the leaky gut” syndrome is formed in the intestine,[40],[41] and “the broken heart” syndrome is formed in the heart.[42],[43] If this process is considered from the standpoint of the effect on the lung endothelium, then peroxynitrite causes its toxic damage with the formation of systemic endotheliosis. Respiratory failure is a clinical manifestation of this process, which is caused by damage to various cellular elements, but especially the endothelium.[44],[45],[46],[47],[48]

In addition, peroxynitrite leads to tyrosine nitration, which, in turn, alters the catalytic activity of proteins, and also leads to the emergence of autoimmune reactions in response to modified proteins.[49],[50],[51],[52] DNA breaks can occur through interactions with nucleic acids.,[52],[53],[54],[55] Peroxynitrite initiates lipid peroxidation of the myelin sheath of nerves, as well as low-density lipoproteins.[56],[57],[58],[59],[60] A number of studies have shown that alpha-synuclein undergoes nitration with the formation of Lewy bodies, characteristic of Parkinson's disease.[61],[62]

It should be noted that peroxynitrite easily passes through the erythrocyte membrane and combining with hemoglobin forms methemoglobin (Met-Hb). Hemoproteins and sulfhydryl groups of amino acids are the main targets of peroxynitrite. This interaction ends with the formation of Met-Hb and nitrotyrosine.[63],[64] It is possible that a decrease in blood oxygenation at the initial stages of the disease is additionally due to the development of hemic hypoxia due to the oxidation of hemoglobin and the formation of ferryl (Hb−FeIV=O)/(Hb−Fe4+=O) or perferrile (Hb−Por*+−FeIV=O)/(Hb−Por*+−Fe4+=O) forms of hemoprotein.[65],[66] By forming compounds (metforms) with oxyhemoglobin and oxymyoglobin, peroxynitrite damages the porphyrin ring, induces protein conformation, and promotes the release of heme from the hydrophilic pocket, and sometimes from the erythrocyte, with the destruction of the latter.[67] Thus, ventilation hypoxia is complemented by a hemic one. Perhaps, the fact of the discrepancy between the volume of lung lesions on the CT scan and the decrease in the level of oxyhemoglobin is explained by that. The last one is declining faster than would be expected based on the volume of the lung injury. Perhaps, this is one of several mechanisms for the development of “silent hypoxia.” Proof of this assumption was found in the work of Naymagon et al. in which the appearance of Met-Hb from 3.0% to 30% was recorded by the authors in severe patients with COVID-19.[68] The author associates the appearance of Met-Hb not with medication, but with the development of oxidative stress. As an effective therapeutic agent, the authors resorted to methylene blue (MeBlu) at a dose of 1–2 mg/kg. It is important that, in this situation, the degree of saturation of hemoglobin with oxygen decreases; however, the oxygen tension in the blood may remain normal or slightly reduced. The effectiveness of MeBlu may be associated not only with its properties to reduce oxidized iron in hemoglobin and with the relief of tissue hypoxia. MeBlu has a whole range of effects that can be used in the treatment of COVID-19 pneumonia: antioxidant, antihypoxic, antimicrobial, and antiviral. The latter effect is associated with the ability of MeBlu to uncouple the S1 protein complex and the ACE2 receptor. For the purposes of this article, it is important to note its ability to inhibit the synthesis of NO. Despite the long history of the use of MeBlu, it is rational and purposeful to study this compound in COVID-19 pathology, specifying the effective doses, time of administration, and duration of treatment. This cheap and low toxic compound could expand the range of effective agents for the prevention and treatment of viral pathology. We have analyzed and selected a number of drugs and compounds that can suppress the formation of NO and inactivate peroxynitrite in case of COVID-19. It may be useful for therapeutic purposes to reduce the negative effects of exposure of NO and its oxidation products in patients with acute respiratory distress syndrome (ARDS) [Table 1].
Table 1: List of basic compounds and drugs that have an inhibited effect on the formation of nitric oxide and inactivation of peroxynitrite

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  The Mechanism of the Onset of “Silent Hypoxia” and the Role of Nitric Oxide Top

It is a strange fact that along with the development of hypoxemia, resuscitators note the absence of an increase in CO2 tension for a long time. The fact can be explained from two points of view: CO2 diffuses 200 times more easily at the level of the lungs, in contrast to oxygen, so its voltage increases only with pronounced disorders of the air–blood barrier. Second, the absence of an increase in CO2 and dyspnea can be explained by the binding of CO2 by peroxynitrite to form nitrosoperoxycarboxylate, which leads to the formation of CO2* and NO2* upon isomerization.[69],[70],[71] However, Spanish scientists believe that the lack of a response in the form of shortness of breath to a decrease in the level of oxygen in the blood is associated with damage to the chemoreceptors of the carotid zone, which are responsible for the perception of the level of O2. It is pertinent to recall that the sensitivity of peripheral chemoreceptors is significantly higher to changes in CO2 concentration than to O2.[72],[73] For example, it is known from the course of physiology that an age-related increase in the concentration of CO2 in the alveolar air by only 0.17% causes a doubling of the respiratory minute volume (RMV), and a decrease in oxygen level by 40% does not cause significant changes of the RMV.[74],[75] Based on this, we assume that the absence of a reaction in the form of dyspnea lies in the absence of an increase in CO2 tension, which is associated, in turn, with the formation of a large number of compounds with peroxynitrite, the concentration of which significantly increases during systemic inflammatory reactions.

Hence, in one of the few reports,[76] it is said that CO2 voltage did not significantly differ in the surviving (33.0–40.5 mmHg) and deceased (33.7–39.8 mmHg) patients. Alkalosis was recorded in 64.3% of patients, and in patients with severe alkalosis (pH = 7.45–7.50 in survivors; 7.40–7.48 in the deceased, P > 0.05), the survival rate was significantly higher. It seems to us that the binding of CO2 with peroxynitrite promoted the development of alkalosis, as well as respiratory compensation in the form of shortness of breath, and the activation of the renal mechanism aimed at enhancing the reabsorption of the bicarbonate anion. Disturbances corresponded to respiratory alkalosis in terms of metabolic component (BE) and CO2 level. Changes in the level of potassium, lactic acid, and sodium were not significant. Another possible mechanism for the formation of alkalosis, in our opinion, is the binding of a hydrogen ion by peroxynitrite to obtain the HOONO compound. It is pertinent to note that in an alkaline environment (as well as a low temperature), the presence of CO2 contribute to the degradation of peroxynitrite;[33],[65],[70],[77],[78] therefore, apparently, the presence of alkalosis contributed to the survival of patients to some extent. These features, as it seems to us, are of great practical importance.

  The Importance of Calcium-Independent Nitric Oxide Synthase Top

Another mechanism for the development of lung damage in COVID-19 is associated with the involvement of calcium-independent NOS activated by cytokines.[6],[7],[79],[80],[81],[82] This leads to excessive vasodilation and tissue damage by stimulating the production of NO, which diffuses into the vessels attached to the alveoli, causing them to relax. It is possible that this determines the fact that there is no increase in the elastic resistance of the lungs at the height of the disease, which is noted by resuscitators. The data of modern research methods using CT scan show signs of dilatation of medium and small vessels in the affected area and, on the contrary, hyperperfusion in nearby areas of the lungs not affected by the virus. In support of this hypothesis, von der Thüsen et al.,[83] found vasodilatation less than 3 mm in the “opaque glass” zones. At the same time, mosaicism of the vascular pattern was observed, probably due to hypoxic vasoconstriction and thrombus formation. A halo of increased perfusion is noted in the peripheral areas of the opaque areas. According to Lang et al.,[84] in severely ill patients, 82% of cases had signs of vascular dilatation. Regional hyperemia passing through and around the area of opacity was noted in 52% of cases. The reaction of the muscle elements of the bronchi and blood vessels probably underlies the absence of an increase in the resistance of the lungs in this pathology.

Inflammatory vasodilation can lead to shunting of blood and aggravated hypoxia. Disorders of microcirculation in the lungs and disseminated microthrombosis provoke metabolic hypofunction of the lungs, especially in the production of antithrombin-III and heparin against the background of progression of damage to the endothelium of the vascular walls.[85],[86],[87],[88] In addition, hyperimmune inflammation leads to uncontrolled activation of coagulation factor Xa, which induces IL-6 expression and cell proliferation in lung fibroblasts, and also leads to systemic thrombus formation not only in the lungs but also in other organs.[89],[90],[91],[92]

In some studies, it has been shown that hypercapnia reduces the phagocytosis of macrophages and also inhibits the synthesis of IL-6 and TNF in an experiment on mouse and human immune cells.[93] These effects were observed quite clearly at a CO2 stress already at values of 64–65 mmHg and especially significantly at pCO2 = 88 mmHg and were not dependent on the oxygen voltage. It is possible that in case of hyperimmune inflammation, its activity can be somewhat reduced by creating dosed moderate hypercapnia and blocking IL-6 must reduce the process of pulmonary fibrosis.

  Therapeutic Uses of Nitric Oxide to Treat COVID-19 Top

The question arises: is SARS-CoV-2 capable of affecting the synthesis of iNOS, eNOS, and nNOS in cells or tissues directly or indirectly? However, according to the published data, the main factor affecting the production of NO and its derivatives is a change in metabolic processes in the body, because of the occurrence of ARDS in COVID-19. Throughout the process of ARDS, cells in the lungs produce a large number of inflammatory factors that increase the synthesis of iNOS in alveolar macrophages, neutrophils, and bronchial epithelium, promoting the release of large amounts of NO in the first stages locally and then systemically. The large endothelial surface, primarily of the lungs, becomes a source of synthesis of large amounts of nitric oxide. Clinical studies have reported a high concentration of NO, as well as its other metabolites in bronchoalveolar tests, not only for patients with an early phase but also in patients at risk of ARDS, until the clinical diagnosis is confirmed.[94],[95],[96],[97]

It is appropriate to stop here on inhaled forms of NO administration as a treatment modality featured today in various FDA protocols for the treatment of COVID-19. These recommendations are based on a 2003 analysis of SARS treatment, but their effectiveness remains to be evaluated.[98] The temporary improvement in blood saturation from inhalation of NO, which is recommended by the FDA, may be associated with increased perfusion of areas of the lungs not involved in the inflammatory process. Patients with an initially high level of intrapulmonary shunt had an improvement in oxygenation when inhaled with low concentrations of NO in the order of 10–40 ppm.[99],[100] However, in the affected areas, inhalation of NO can exacerbate the extent of the injury. The currently recommended NO inhalation against the background of active inflammation can be accompanied by the formation of toxic compounds of NO metabolism, for example, peroxynitrite.[101],[102] The absence of the difference in patient survival from the use of this technique indicates the presence of controversial issues in the proposed therapy.

Contrary to the FDA recommendations, it was shown in a number of works that the use of blockers of NOS inducers had a positive effect on the course of the inflammatory process. It was shown in experiments on mice that iNOS-positive mice survived more often than iNOS-negative mice when infected with a small number of Toxoplasma gondii cysts.[103] However, it had been recorded the opposite picture when exposed to large doses of the pathogen, i.e. iNOS-negative animals survived.[104] Bogdan[105],[106] has shown that iNOS expression correlated with disease progression in various infections. For example, in an experiment on rabbits with induced myocardial infarction, there is an insignificant decrease in NO in the first 2 h and then an increase in it by two times and subsequent maintenance of this level for 24 h.[107]

It is logical to assume that the reaction of the vascular zones of the lungs has phasing and changes in time: In the initial stages, an improvement and increase in blood circulation occurs; and then, there is a disorder of the physiological mechanisms of ventilation and perfusion, as well as a disorder of microcirculation with the development of endothelial dysfunction, thrombosis, and inflammation. Based on the above, we can conclude that with a large infection, a compensatory increase in NO production does not provide antiviral protection and physiological regulation of vascular tone, and the formed metabolites, in particular peroxynitrite, aggravate the damaging effect of inflammation and enhance it.

In our opinion, one of the reasons for the ambiguous response, when using inhaled forms of NO, is in the absence of time parameters for the use of inhalation, based on the severity of clinical manifestations, the extent of the process, and the laboratory data. According to the published data, there are several phases of inflammation in COVID-19: early phase of infection, pulmonary phase, and severe hyperinflammation phase. From the first symptoms to the formation of the ARDS, it takes an average of 8 days. Patients have excessive activity of CCR6+ Th17 cells and CD8+ T cells, which is accompanied by damage to the lung structures. High levels of cytokines (IL-1β, IL-6, IL-12, IL-18, IL-33, TNF-α) and chemokines (CCL3, CCL5, CXCL8) cause “a cytokine storm.” In severe forms, there are a decrease in IL-10 and an increase in serum IL-6. It was found that high mortality is associated with high levels of IL-6.[108],[109],[110] Undoubtedly, during this period, the synthesis and formation of NO and metabolic products are activated as a complex of the antiviral defense of the body.

Therefore, it may be more rational to use NO for inhalation in the early stages of the disease (1–7 days), with moderate severity (early and pulmonary phases), and in the presence of evidence of improved oxygenation rates. In all likelihood, such therapy would be advisable at the stage of regression of the process in the lungs, including the rehabilitation period. The use of NO during the “cytokine storm” (the phase of hyperinflammation), in all likelihood, should be considered unreasonable due to the activation of the oxidation process and the formation of toxic products of NO metabolism.

It is known that oxidative stress activates the synthesis of endogenous antioxidants from the endothelium: glutathione peroxidase-1, catalase, superoxide dismutase-1; the factor associated with erythroid nuclear factor 2 (NRF2).[111] In hyperinflammation, there is a deficiency of antioxidants, which justifies the use of compounds with antioxidant properties. The amount of nitrite and N-nitroso compounds (RNNO) in the inflammatory process increases sharply due to NO donors under the influence of reactive oxygen species formed from activated leukocytes.[112],[113],[114] Under physiological conditions, this does not happen and NO diffuses into the extracellular space by connecting with its receptors of target cells. However, the inflammatory process significantly increases the content of nitrite and nitrate, as well as N-nitroso compounds in the blood plasma. This fact allowed Titov et al.[115] to propose the definition of these compounds as a marker of inflammation although the methods for the determination of these compounds themselves require improvement. At the same time, the concentration of these metabolites turned out to be a more sensitive marker for assessing the intensity of the inflammatory process than the number of leukocytes, ESR. Today, the borderline concentrations of nitrite and N-nitroso compounds (150 nM) have been determined with a favorable course of the inflammatory process. The conclusion suggests itself that it is advisable to use inhibitors of NO synthesis during the period of hyperinflammation.

  The Role of Nitric Oxide in Brain Damage in COVID-19 Top

Another aspect to be highlighted in this article is related to the pathological processes occurring in the brain during COVID-19 and the role of NO. The issue of virus damage to the central nervous system (CNS) and peripheral nervous system remains poorly understood, but it may be important in understanding the consequences, as well as of the prediction of brain function in persons who have undergone COVID-19.

According to the published data and the opinion of the authors, the virus can penetrate into the structures of the CNS most likely through the olfactory nerve, using presumably axonal transport and transsynaptic transport. Loss of smell at the initial stages of the disease may be the result of damage to the afferent fibers of the olfactory nerve. The second way the virus enters the brain is the hematogenous one.[116],[117],[118] Apparently, not only the olfactory nerves can be affected but also other afferent fibers, which serve as the gateway for the infiltration of the virus into the brain. Retrograde transport of the virus from the lungs, using n. vagus afferent fibers, chemo- and mechano-receptors of the nucleus of a single tract, with subsequent damage to the structures of the respiratory center, is not excluded.[72],[119],[120] Currently, a huge anti-inflammatory and integrating role of the dorsal vagus nerve complex has been established, which is carried out along the efferent fibers of the vagus nerve by means of acetylcholine.[121] Attention should be paid to the fact that impaired afferentation (vagotomy) leads to pulmonary tissue edema.[122],[123] In all likelihood, the receptor role of J-receptors, signaling the amount of fluid in the interstitial space, is disrupted. At the stage of activation of proinflammatory cytokines and the infiltration of the virus into the CNS, inflammatory processes in the neurons of the vagus nerve can increase the production of acetylcholine and accordingly increase the synthesis of NO. Responsible for this are receptors for IL-1, which are found on the neurons of the vagus nerve and the nuclei of the solitary tract.[123],[124],[125] Virus damage or neuronal excitation by cytokines of the motor nucleus of the vagus nerve (nDX) and the nucleus of the solitary tract can induce “neurogenic pulmonary edema,”[126] in whose genesis pathological changes in the neurohormonal link in the regulation of water–salt metabolism in the lungs were found. The factor aggravates the existing hypoxia and disrupts the production of surfactant and anticoagulants. The relationship between peripheral inflammation and the activity of the anti-inflammatory system of the vagus nerve is likely to be established via IL-1.[124],[125] All organs of the reticuloendothelial system have a representation of the vagus nerve, which significantly changes the course of inflammation, and phagocytes, in particular macrophages, have receptors for acetylcholine, noradrenaline, IL-1, TNF-α, etc.[127],[128] Muscle fatigue in the post-COVID period, noted by the majority of patients, may be associated with a disturbance in the “acetylcholine-receptor-acetyl cholinesterase” system.

Activation of the inflammatory reaction in the brain cells provokes the penetration of T-lymphocytes and granulocytes from the cerebral vessels into the subarachnoid space. This is facilitated by the so-called “adhering molecules” of various types, which are synthesized in the endothelium.[129],[130],[131] The interaction of lymphocytes with endothelial cells is a signal for the production of NO.[10],[132],[133] In addition, the hematogenous drift of the virus and its infiltration into the endothelial cells of the vascular membranes of the brain is a factor contributing to the inflammation of the endothelium and an increase in the synthesis of NO. The resulting edema of the endothelial cells of the arachnoid membrane, as well as the excessive production of cytokines in the neuroglia, often causes persistent and severe headaches. There are nociceptive neurons in the brain that are excited by inflammatory cytokines; however, NO acts as a mediator (nonadrenergic, noncholinergic) of inflammation at all stages of inflammation.[134],[135],[136] Increased production of NO can be assumed by the pathological finding, which is observed in those who died from viral pneumonia. In the structures of the brain, there are areas of increased vascular permeability with foci of micro- and macro-bleeds, including areas with signs of ischemic lesions.[137],[138] Such mosaicism may indicate the phase character of the process and different degrees of damage to the system of synthesis and utilization of NO and its oxidation products.

Despite the presence of the blood–brain barrier, the brain is involved in the systemic inflammatory response. The anti-inflammatory cholinergic function of the parasympathetic system is depleted under conditions of active production of cytokines and NO. Its effectiveness in inhibiting the synthesis and release of TNF-α, IL-1, and other cytokines in macrophages becomes inconsistent.[115],[127],[128],[139] Cytokines, peptides, and immunomodulators, which are synthesized in excess by lymphocytes, do not provide adequate feedback between the organs of the immune system and the brain, which significantly aggravates the pathological process in the CNS.

  Conclusion Top

Thus, there is reason to believe that in the pathogenesis of COVID pneumonia and multiple organ dysfunction, additional significant factors in the genesis of the “cytokine storm” are free oxygen radicals, NO metabolic products, in particular, peroxynitrite. It should also be noted that the overproduction of peroxynitrite aggravates the severity of the COVID infection and causes the so-called “nitrosative stress,” which is the basis for the development of a whole spectrum of pathological processes in the body: neurodegenerative diseases, rheumatoid arthritis, diabetes mellitus, etc., In conclusion, it should be noted that further research is needed to understand the mechanisms of NO functioning and to develop approaches with which it is possible to control its metabolism. From these positions, the development of screening methods for the determination of peroxynitrite and its decay products as a control of the activity of the inflammatory process and the effectiveness of treatment could become promising.

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