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13HYPEROXIC SANOGENESIS OF LUNG GAS EXCHANGE FUNCTION IN SARS-Co-2-
ASSOCIATED PNEUMONIA
Savilov P.
Doctor of Medical Sciences, Professor, Anesthesiologist-resuscitator Tambov Central District Hospital, Tambov Region, Russia
Abstract
The article discusses some mechanisms of the therapeutic effect of hyperbaric oxygenation in COVID-19: the effect of hyperbaric oxygen on the contractility of endotheliocytes of pulmonary capillaries, thrombogenic and arthrombogenic potential of pulmonary vessels.
Keywords: hyperoxia, lungs, SARS - Co-2 - associated pneumonia, treatment
In 2020, Chinese doctors reported the first successful use of hyperbaric oxygenation (HBO) at the Wuhan River Shipping Company hospital in five patients with severe respiratory failure caused by the development of SARS - Co-2 - associated pneumonia. At the same time, independently of this message, the first theoretical works were published, which from a patho-physiological point of view justified the expediency of including HBO in the treatment of patients with COVID [1,2]. After that, new articles began to appear about the use of HBO in this pathology [3-12]. However, the mechanism of therapeutic action of hyperbaric oxygen therapy in this pathology was not subjected to a deep analysis in them. The therapeutic effect of HBO was interpreted from the position of the substitution effect of hyperbaric oxygen. The first is based on the absence, for certain reasons, of experimental data on the effect of hyperbaric oxygen (HBO2) on the leading links in the pathogenesis of SARS - Co-2 - associated pneumonia. The second one is based on the stereotypical thinking about the antihypoxic effect of HBO, by which the authors understood the elimination of hypoxia by hyperbaric oxygen [3-12]. Meanwhile, it is noted only during the session, when the plasma is over-saturated with oxygen in the blood plasma makes red blood cells "unnecessary" for a while. Therefore, in this case, we need to talk about the substitution effect of HBO [13], and such indicators as blood saturation (So2) and oxygen tension (Po2) in assessing the effectiveness of HBO therapy should not be considered in isolation from other clinical, physiological and biochemical indicators. Currently, there is a sufficient amount of data that the termination of the HBO session can lead to restoration, hypoxia and (or) hypoxemia [14,15,16], which does not affect the therapeutic effect of HBO2
[17,18,19]. Based on the above, the question involuntarily arises: what determines hyperoxic sanogenesis in HBO SARS-Co-2-infected patients?
Before answering this question, we will understand the term hyperoxic sanogenesis. The concept of "sanogenesis" expresses a complex of mechanisms of recovery/recovery of the body in any nosological form of the disease [13]. From the point of view of a doctor, hyperoxic sanogenesis is a set of mechanisms that increase the sanogenic potential of both a healthy and a sick organism as a result of its over-saturation with oxygen. HBO2 is a natural evolutionary adaptogen [13]. Therefore, it is a universal factor that can correct the adaptive autorgeulation of the vital processes of a healthy and sick organism.
If we turn to the data of O. A. Levina et al. [18], we will see the following. After the first session of HBO in patients with SARS-Co-2-associated pneumonia (according to computed tomography (CT), lung damage of 3-4 degrees), SO2 was within 99%, i.e. in HBO conditions, hypoxemia, which was noted in the prehyperoxic period, was eliminated. By the second HBO session, the SO2 value significantly exceeded the same indicator at the time of the first HBO session, but was below the norm (Fig. 1), i.e. after the first HBO session, hypoxemia was restored. Hypoxemia in the pre-hyperoxic period was observed before the 7th session of HBO (Table 1). Analysis of the results obtained by O. A. Levina et al. (Table 1), allows us to talk about some biological effects of HBO2, which are manifested during the course of the use of HBO (1,4-1,6 ATA, 40650 min) in patients with SARS-Co-2-associated pneumonia with lung damage of 3-4 degrees (under CT data).
Table 1.
Blood oxygen saturation during the course of hyperbaric oxygenation in patients with SARS-Co - 2__associated severe pneumonia (22 patients) [18]._
Research time HBO session number
1 2 3 4
Before HBO 90 [88;92,8] 92,5* [87,8;96,3] 92,5* [90;95,8] 94* [90;96,5]
After HBO 99# [97,3;100] 99 [94,8;100] 99 [97;100] 99 [97;100]
Research time HBO session number
5 6 7 8
Before HBO 94,5* [92;96,3] 93,5* [93;97] 95* [93;95,5] 95,5* [94,5;96,3]
After HBO 99 [97,3;100] 99,5 [98,8;100] 99 [98,5;99,5] 100 [99,8;100]
Note: * - statistically significant difference from the initial indicator in the group (Wilcoxon criterion, p<0.05); # - statistically significant difference between the indicator "before" and "after" (t- критерий Стьюдента, р< 0,05). On the abscissa axis - the number of the HBO session, on the ordinate axis-blood saturation in %. [18]
First, it is the absence of hypoxemia in patients after extraction from the pressure chamber, regardless of the value of SO2 at the time of oxygenation and the number of HBO sessionsWe have already said that during the HBO session, the elimination of hypoxemia is determined by Henry's law. But how to explain its absence in the first minutes after removing the patient from the pressure chamber, when Henry's law is no longer valid. It is well known that in the process of decompression, carried out at the end of the session before removing the patient from the pressure chamber, desaturation occurs, which is accompanied by a decrease in the oxygen voltage (Po2) in the blood and tissues to the initial value or even lower. But in the studies of O. I. Levina et al. (table.1), in oxygenated patients with SARS-Co-2-associated pneumonia, the SO2 value after each session was in the range of 99-100%. How to explain it?
We consider the statement about the deposition of a certain amount of oxygen in the tissues of an oxygenated organism, as indicated by some authors [20], to be incorrect. Deposition in biological systems is an organized process of long-term storage of a biological substance (for example, the deposition of glycogen in hepatocytes). Meanwhile, the saturation of biological fluids with oxygen during a HBO session is solely the result of physical (hyperbaric) effects on the body, the termination of which leads to desaturation and a decrease in P02, increased in HBO conditions. The increase in this indicator in comparison with the prehy-peroxic state is the result of either the elimination of the factors that caused its decrease, or a decrease in oxygen consumption by cells of a particular organ or tissue.
Discussing the dynamics of SO2 in patients with SARS-Co-2-associated pneumonia, it should be noted that the pulse oximeters currently used for its measurement are based on the two-band absorption spectros-copy method developed by Takuo Aoyagi [21]. This method assumes that the intensity of light absorption by other tissues (except arterial blood) is a constant value that does not change in a particular person during the study time [21]. he pulse wave signal is created only by pulsating arterial blood, fading as the microvessels are filled with blood during systole and increasing during diastole. Since arterial blood predominates in the mi-crovessels at the end of the systole, it is believed that the pulse oximeter registers the saturation of arterial blood [21]. Therefore, the reason for the preservation
of SO2 in oxygenated SARS-Co-2-associated pneumonia in the range of 99-100% (Table.1) in the first minutes after decompression (the body is no longer over-saturated with oxygen) it is not an improvement in the diffusion ability of the lungs. This is due to an increase in blood filling of peripheral tissues as a result of the termination of the evolutionarily determined vasoconstrictor effect of hyperoxia on the peripheral vessels of the large circulatory circle [22] and the development of short-term posthyperoxic vasodilation in them.
Secondly, the HBO course applied by O. A. Lev-ina et al. in patients with SARS-Co-2-associated pneumonia, a decrease in the degree of hypoxemia (determined by the value of SO2) in the prehyperoxic period was revealed as the number of HBO sessions increased from one to six (Table 1). It is this biological effect of HBO2 that indicates a gradual improvement in the diffusion capacity of the affected lungs in patients with SARS-Co-2-associated pneumonia in the process of increasing the quantitative hyperoxic load. It is no coincidence that, according to O. A. Levina et al., 32% of oxygenated patients with SARS-Co-2-associated pneumonia refused additional oxygen therapy during the course of HBO, 41% of oxygenated patients with SARS-Co-2-associated pneumonia had a transition to spontaneous respiration within 1-2 days after completing the course of HBO [18]. How does the gas exchange function of the lungs improve in patients with SARS-Co-2-associated pneumonia during the course of HBO use?
To answer this question, we first turn to the structural features of the alveolar capillary membrane (ACM) and the mechanisms of violation of the diffusion ability of the lungs in acute respiratory distress syndrome (ARDS). Последний имеет место и при SARS- Co-2- ассоциированной пневмонии. According to modern research, the ACM has two sides: "thin" and" thick"." [23]. On the thin side, the endothelial basement membrane "merges" directly with the epithelial basement membrane (there is almost no interstitial here). This side of the AFM is adapted for the diffusion of gases (Fig. 1). The other part of the ACM (Fig. 1), the "thick section", contains almost the entire alveolar interstitial connective tissue. It is designed for the exchange of fluid between the blood and the pulmonary interstitium [23]. Since the intercellular contacts between alveocytes are more dense than between the en-
dotheliocytes of the pulmonary capillaries, in physiological conditions, soluble compounds larger than urea do not leave the alveolar interstitium into the alveolar cavity. The absence of water in the spaces of the alveoli of a healthy lung with its mandatory presence in the alveolar interstitium is associated with the functioning of three compensatory mechanisms: the sieve effect, the phenomenon of increased interstitial hydrostatic pressure and the reserve capabilities of the pulmonary lymphatic system [23]. he analysis of morphological changes in the lung tissue that occur during the devel-
opment of SARS-Co-2-associated pneumonia [24] suggests that changes in the microcirculatory bed of the lung tissue in this pathology will be identical to those described in the experimental modeling of local inflammation: a) reduction of endothelial cells; b) reorganization of their cytoskeleton and the contact of these cells; c) endothelial damage with retraction, lysis and detachment; d) endothelial detachment without lysis [25]. The difference will be only in the features of the triggering mechanisms and the nature of the development of the inflammatory process in the tissue with a cytokine storm or in its absence [25,26,27].
Fig. 1. Functional anatomy of the alveolar-capillary membrane. The liquid enters the interstitial space from the "thick" side of the membrane." The thin side of the membrane is ideally adapted for gas exchange. According to
the drawing John Hansen-Flaschen (1997) [23].
The analysis of clinical reports that have shown the high effectiveness of HBO in the treatment of SARS-Co-2-associated pneumonia [3-12] suggests that HBO2 is a sanogenic intervention not only in the processes of origin and development as a cytokine storm, but also the final stage of its activity, manifested by a violation of the function of external respiration and gas exchange in the lungs. he huge material accumulated over the past decades on the successful use of HBO in various branches of medicine gives reason to believe, that in patients with SARS-Co-2-associated pneumonia, a direct, indirect and reflex effect of HBO2 on pathological, protective-adaptive and compensatory reactions occurring in the body with this type of pathology should be expected.
According to Leonov's theory of hyperoxic sano-genesis, the therapeutic effects of HBO2, regardless of the state of the body at the time of oxygenation, are based on adaptive-metabolic, adaptive-functional and adaptive-morphogenetic mechanisms, which are implemented at different levels of the structural and functional organization of the body [13]. Therefore, forming our ideas about the processes that underlie the elimination of HBO2 violations of the gas exchange
function of the lungs in SARS-Co-2-associated pneumonia, we will first try to understand its effect on the structural and functional unit of the lung tissue-aci-nus[28]. In addition to the alveoli, it includes capillaries of blood and lymphatic vessels, extracellular matrix( ECM), bronchioles and nerve endings.
It is known that one of the first targets of the damaging effect of cytokines are vascular epithelial cells [25], the reduction of which increases the permeability of the capillary wall to liquid and plasma proteins (but not blood cells) [23]. he development of this process in endotheliocytes of the thick part of the ACM will lead to an increase in the flow of water and plasma proteins from the blood into the pulmonary interstitium through enlarged intercellular gaps against the background of impaired functioning of vesicular channels in endothe-liocytes. ( The latter are formed as a result of temporary mergers of invaginations of cell membranes and cyto-plasmic vesicles [23]) and vesicular transcytosis. As for the thin part of the ACM, here, due to the morphological features of its structure (Fig.1), endotheliocytes should be expected to swell at the beginning as a result of an increase in the permeability of their plasma membrane caused by the action of cytokines. (Initially, this process will begin in alveocytes affected by SARS).
Since intracellular hyperhydration is accompanied by a violation of cell functions, its development in the endo-theliocytes of the pulmonary capillaries will lead to a decrease in their anti-adhesive properties. As a result, the adhesion of platelets, neutrophils and plasma proteins to them. The thin section of the ACM in the area of inflammation will turn into a thick one, which will affect the rate of gas diffusion through it. As the pathological process progresses, damage to both parts of the ACM will occur in the lung tissue with the release of both the extravasal space and the lumen of the alveoli of shaped blood elements, primarily neutrophils, with the formation of extensive infiltrates [24].
It was found that the use of HBO2 in diabetes mellitus, liver transplantation and as a preconditioning inhibits the formation of pro-inflammatory cytokines TNF-a, IL-1P, IL-6 [29-33], which, as is known [34], are formed in addition to respiratory epithelial cells and in pulmonary macrophages. Therefore, there is every reason to expect a similar effect in oxygenated patients with SARS-Co-2-associated pneumonia. It will be based not only on a shift in the ratio of pro - and anti-inflammatory cytokines towards the latter, including
through the" transformation " of pro - into anti-inflammatory cytokines, but also an increase in the pool of cells refractory to cytokine storm stimulators.
t can be assumed that the following mechanisms of hyperoxic influence on the contractility of endothelial cells of pulmonary capillaries in SARS-Co-2-associated pneumonia (Fig. 2): 1. Suppression of HBO2 production of proinflammatory cytokines Il-1 and tumor necrosis factor (TNF), which, as is known [25], activate the formation of thrombin and fibrinogen, causing the contraction of endothelial capillary cells; 2. Violations of the interaction of calcium with cal-modullin, which will prevent the reaction of endotheli-ocytes of both parts of the ACM to the stimulation of their retraction. 3. Violation of the adhesion of thrombin and fibrinogen on the surface of endotheliocytes of the pulmonary capillaries under the influence of HBO as a result of the blockade of the adhesive receptors of endotheliocytes by endogenous metabolites evolution-arily programmed for an adaptive reaction of the body in response to its over-saturation with oxygen. One of them may be urea, the formation of which in the lungs increases with therapeutic HBO regimens [35,36].
Figure 2. Diagram of the proposed mechanism of hyperoxic effect on the contractility of endothelial cells ofpulmonary capillaries in SARS-Co-2-associatedpneumonia
HBO2-hyperbaric oxygen, EC-endotheliocytes, MPh-macrophages, NPh-neutrophils TNF- tumor necrosis factor, IL-1 interleukin 1. Red solid arrow -stimulation of the process, red intermittent arrow-inhibition of the process, yellow arrow - inhibitory effect of HBO 2, endogenous blocker of adhesive receptors of endotheliocytes
of pulmonary capillaries
The ability of HBO to cause ultrastructural changes in cells associated with the relief of the inflammatory process in the organ is known [13]. Therefore, we can talk about the ability of HBO2 to both prevent and exert a regulatory effect on changes in the cytoskel-eton and intercellular contacts of alveocytes and endothelial cells of both parts of the ACM, which occur during a cytokine storm. The end result of this will be the prevention of endothelial detachment from the basement membrane and the normalization of diffusion processes in it.
One of the morphological signs of severe inflammation in the lungs, including in SARS-Co-2-associated pneumonia, is the death of alveocytes and endotheliocytes [24, 25]. The reason is cell autolysis as a result of increased permeability of lysosome membranes. This leads to the release of lysosomal enzymes from them into the cytoplasm and self-digestion of the cell. Meanwhile, HBO in therapeutic regimens stimulates the accumulation of urea in the lungs both in normal [35] and in pathological conditions [36], which is a stabilizer of lysosomal membranes [37], preventing the release of lysosomal enzymes into the cell cytoplasm. The ability of urea to inhibit the formation of oxygen radicals on iron-containing proteins should be noted [38]. From these positions, it can be argued that similar HBO regimens will have an inhibitory effect on the autolysis of lung tissue cells in SARS-Co-2-associated pneumonia.
It is known that SARS affects type II alveocytes [39], which are responsible for the production of surfactant. The death of these cells, as well as a violation of the synthesis of surfactant, leads to the collapse of the alveoli, so its shutdown from gas exchange, his is
caused by the activation of free radical processes and lipid peroxidation (LPO) in the lung tissue found in respiratory distress syndrome (APDS) [34], which also develops in SARS-Co-2-associated pneumonia [39].
To date, the ability of HBO to prevent increased generation of free radicals has been established (it was first described by V. A. Barsukov in 1968 [40]) and to inhibit the activation of LPO in conditions of pathology [41]. In addition, the high resistance of the enzyme department of the antioxidant system of intact lungs to 18-day hyperoxic load with single HBO sessions in the 2 ata, 50 min mode was revealed [36], which are also used in the treatment of SARS-Co-2-infected patients [18]. All this allows us to assert the inhibition of excessive lysis of ACM endotheliocytes in oxygenated patients with SARS-Co-2-associated pneumonia. This therapeutic effect of HBO2 can be realized in several ways: direct and indirect (Fig. 3)
The direct effect of HBO2 will be manifested by its influence on the respiratory chain of mitochondria, changes in the consumption of oxygen by cells under hyperoxia conditions, which, as established [13], is directly dependent on their functional state at the time of oxygenation. Since cells with different degrees of functional activity are found in the inflamed tissue [25], the rate of oxygen consumption by them will be different: increased, reduced, or refractory. Based on this, the rate of natural leakage of reactive oxygen species (ROS)will also change in the conditions of HBO: the increased is inhibited, the reduced is normalized. his will naturally affect the activity of enzymes of the antioxidant system, especially superoxide dismutase (SOD) of the lungs, which has revealed high lability when adapting to hyperoxic load [36,42].
Figure 3. Proposed mechanisms of action of hyperbaric oxygen on free radical processes and cell membranes of
the endothelium of pulmonary capillaries and alveocytes AC - alveolocytes, RCh-respiratory chain, EC-endothecliocytes, HBO2-hyperbaric oxygen. Red color - stimulation of the process, yellow color - inhibition of the process, green color-natural flow of the process, black color-no influence on the process, blue color - regulating influence on the process.
In the cytosol of endotheliocytes of pulmonary capillaries and pneumocytes, urea and uric acid can act as a regulator of the formation of ROS in hyperoxia. It is no coincidence that these components of the non-enzyme link of the antioxidant system of the lungs reacted in the experiment to an increase in the hyperoxic load with HBO treatment regimens [35] used in patients with SARS-Co-2-associated pneumonia [18]. In addition, the ability of HBO to inhibit lipid peroxidation and activate the antioxidant system in the lung tissue in hemorrhagic shock was revealed [43].
The indirect effect of HBO will be realized through a change in the metabolism in the alveocytes of the glutamine and glutathione cycles. The first one supplies a substrate for the synthesis of glutathione, the second one neutralizes hydrogen peroxide. Prevention of excessive formation of reactive oxygen species and hydroperoxides by the cells of the affected organ in hy-peroxic conditions is one of the conditions for inhibiting LPO [13]. As a result, the increased resistance of plasma membranes to the action of damaging factors and the rapid restoration of their damaged areas in the process of intracellular regeneration. This will also be facilitated by a change in the content of phospholipids in them during the hyperoxic effect. In the experiment, it was found that the use of HBO in hemorrhagic shock stimulates the accumulation of phosphatidylinosite and sphingomyelin in the lung tissue [43], which, as is known, provide "rigidity" of cell membranes.
One of the leading links in the pathogenesis of impaired lung gas exchange function in ARDS, developing against the background of SARS - Co-2-associated pneumonia, is a violation of microcirculation in the lungs as a result of the development of thrombotic microangiopathy and thrombosis [44]. It was found that an increase in the concentration of proinflammatory cytokines IL-1a, IL-6, TNF-a in the blood causes expression on the endothelium, monocytes and macrophages of tissue thromboplastin-the trigger of coagulation [3 9]. In this case, the von Willebrand factor is released from the endothelium, leading to adhesion and aggregation
of platelets on the walls of blood vessels. The expression of tissue thromboplastin promotes the transition of factor VII to VIIa, which leads to the activation of factor X. At the same time, factor Va is released from the activated platelets, forming a complex with the Xa protein, which transforms prothrombin into thrombin [39]. Pro-inflammatory cytokines cause a decrease in endogenous anticoagulants in the blood - an inhibitor of the external pathway of tissue factor, antithrombin III and activated protein C [44,45]. The interaction of endotheliocytes, platelets, monocytes, macrophages, lymphocytes and leukocytes in the" cytokine storm " increases the expression of tissue factor and enhances coagulation [45].
Meanwhile, the positive results obtained in the treatment of SARS-Co-2-associated pneumonia by the HBO method [3-12, 46] suggest the possibility of HBO2 to eliminate (prevent) pathological tromob formation in the microcirculatory bed of the lungs. To date, a small amount of work has been accumulated on the effect of HBO on individual links of hemostasis. However, it was noted that the ability of HBO2 to stimulate or suppress tromob formation depends on the state of hemostasis at the time of oxygenation [47,48,49]. For example, the use of HBO against the background of hypercoagulation led to the normalization of the co-agulogram [49,50]. We will try to understand some of the mechanisms of the therapeutic effect of HBO2 on thrombotic microangiopathy in the pulmonary capillaries in SARS-Co-2-associated pneumonia. In this paper, we will address the issue of the hyperoxic effect on the thrombosis resistance of the pulmonary capillaries, which is determined primarily by the functional activity of their endothelium [51]. It was found that vascular endothelial cells secrete both thrombogenic (thromboplastin, fibronectin, Willebrandt factor, thromboxane A2, platelet activation factor) and atrambogenic factors (Proteins C and S, thrombomodulin, proteoglycans, heparin). Let's consider one of the possible mechanisms of hyperoxic influence on the thrombogenic activity of the pulmonary capillary endothelium in the conditions of thrombogenic microangiopathy caused by SARS-Co-2 (pnc.4).
Figure 4. Suggested mechanisms ofhyperoxic effect on the thrombogenic activity of the pulmonary capillary vascular wall in hypercoagulation caused by SARS-Co-2 infection HBO2-hyperbaric oxygen, TrA2-thromboxane A2, TrP-thromboplastin, Trn-thrombin, FN-fibronectin, f.W-Wil-librand factor, PAF-platelet activation factor, AAC-arachidonic acid cycle, IL-1- interleukin, LN - leucotrienes. Red solid arrow - stimulation, red intermittent arrow-inhibition, blue arrow-stimulating effect of HBO2, yellow arrow-inhibitory effect of HBO2 - inhibition of the process, X-HBO2-deterministic violation Having the ability to inhibit the release of pro-in- It is known that the main sources of plasma fibron-
flammatory cytokines [29-33], HBO2 will prevent their ectin are vascular endothelium and hepatocytes. Dam-
damaging effect on the cell membrane, which triggers the synthesis of thromboplastin by endotheliocytes. Thromboplastin in physiological conditions is formed in them slightly or does not form at all [52,53]. We do not exclude HBO-deterministic inhibition of the release of the formed thromboplastin to the surface of the en-dothelial cell with its subsequent cleavage into protein and lipid fractions. These fractions do not have procoagulant activity [54,55].
Thromboplastin localized on the cell membrane not only activates hemocoagulation, but also binding to heparin reduces its anticoagulant activity [56]. It is known that the binding of urea to heparin increases the anticoagulant properties of the latter [57], and HBO stimulates the formation (accumulation) of urea in the lung tissue [35,36]. Therefore, it cannot be excluded that by interacting with heparin, urea prevents its binding to thromboplastin localized on the endothelium of the pulmonary capillaries (pnc.4).
It can be assumed that by eliminating the damaging effect of cytokines on the cell membrane, HBO2 will simultaneously increase its resistance to the action of damaging factors. As a result, increased formation of thromboxane A2 by endotheliocytes is prevented. At the same time, its inhibitory effect on the release of thromboxane A2 from cells and its intracellular degradation is not excluded.
age to the capillary wall is one of the signals to activate the formation of fibronectin by endotheliocytes. Thrombin stimulates the release of fibronetkin by en-dothelial cells, without affecting its synthesis in them
[58]. By binding to glycoprotein III on the surface of activated platelets, fibronectin promotes their rapid aggregation and adhesion. For the normal course of blood clotting, fibronectin is not a necessary factor, but when hemocoagulation is activated, it is involved in the process of clot formation, forming a covalent bond with the a-chain of fibrin [51].
It can be assumed that HBO2, preventing damage to the cell membrane by cytokines, will inhibit the effect of thrombin on the output of fibronectin from the cell. The restoration of the cell membrane under the influence of HBO will lead to the termination of signals from its damaged areas, provoking the stimulation of fibronectin formation. We do not exclude that the change in blood pH occurring under HBO conditions
[59] will have an inhibitory effect on the dissociation of surface fibronectin (Fig.4We do not exclude the stimulating effect of HBO on the flow of fibronectin from the blood into the capillary endothelium (Fig. 4), which was found in physiological conditions [60].
It is known that pro-inflammatory cytokines stimulate the synthesis of platelet activation factor (PAF) [61]. n the absence of stimulation, endotheliocytes do
not form or form in very small quantities [51]. It can be assumed that in platelet microangiopathy, HBO2 will eliminate this phenomenon, as well as inhibit the release of already formed PAF into the bloodstream (Fig.4). similar effect of HBO2 can have on the formation of PAF in other lung tissue cells involved in the inflammatory process (mast cells, neutrophils, alveolar macrophages).
One of the main factors determining the adhesion of platelets to the vascular wall of the capillary is the Willibrand factor, which is synthesized and accumulated in endothelial cells as part of the Weibel-Palade bodies. he level of Willibrand factor in endotheliocytes can be affected by both signals coming from other cells [62] and thrombin. Thrombin stimulates its secretion, causing the methylation of fisphatilylethanolamine and the entry of Ca2+ into the cell [51]. It can be assumed that HBO2 will inhibit the secretion of Willibrand factor by endothelial cells into the bloodstream by the following mechanisms: a) changes in the affinity of pulmonary capillary endotheliocyte receptors for thrombin 6) regulation of Ca2+ entry into cells. Hyperoxic stimulation of the deposition of the Willibrand factor inside them is also not excluded. This, according to the feedback principle, will lead to a temporary cessation of the formation of this substance.
In addition to thrombogenic factors, factors that inhibit blood clotting, activate fibrinolysis, and inhibit platelet aggregation and adhesion are formed in the vascular endothelium. These factors form the atrombo-genic potential of the vessels, which are provided by the blood flow in the microcirculatory bed. A decrease in
this potential, as a result of damage to the vascular en-dothelium against the background of hypercoagulation - is a direct path to thrombogenic microangiopathy, capillary thrombosis and organ dysfunction, which occurs in severe COVID-19 [39].
An important role in the formation of the atrom-bogenic properties of blood vessels is assigned to the protein C-thrombomodulin-protein S system. Protein C (PrC) is a vitamin K-dependent protein formed in the liver. Anticoagulant properties are shown only by the activated form (A-PrC). The natural activator of PrC is thrombin, but for rapid activation, it is necessary to have a membrane protein of endothelial cells - throm-bomodulin, which is integrated into the composition of the endothelial cell membrane [51]. The proteolytic activity of A-PrC is significantly enhanced in the presence of another vitamin K-dependent protein-protein S (PrS), which, in addition to hepatocytes and endotheliocytes, is contained in alpha-granules of platelets [51]. The interaction of PrC, thrombin, thrombomodulin and PrS occurs on the cell membrane of the endothelial cell. Damage to it during a cytokine storm will certainly affect the coagulation potential of the blood and the tro-moboresistance of the vessels. In particular, a decrease in the content of PrS in the blood was found in ARDS [51]. The ability of HBO to eliminate violations of the protein-synthetic function of the liver caused by hypoxia [13], which also develops in severe COVID-19 [3-12], suggests the stimulation of HBO2 of the formation of PrC in the liver of patients with SARS-Co-2-associated pneumonia (Fig. 5). At the same time, spontaneous activation of the PrC located in
Figure 5. The proposed mechanism of the regulatory effect of HBO2 on the atrombogenic properties of the endothelium of pulmonary capillaries in the protein C-thrombomodulin-protein S system during hypercoagulation
caused by SARS-Co-2 infection HB02- hyperbaric oxygen, A-PrC - the active form ofprotein C, PrC - protein C, IPA - an inhibitor of the plasminogen activator, GC - the Golgi complex, PrS - protein S, TM - thrombomodulin, Trn - thrombin. Red color -stimulation of the process, yellow color - inhibition of the process, X-HBO-deterministic violation
the plasma, which occurs with the participation of thrombin and Ca2+, is not excluded. ( Thrombin is a natural activator of PrC; it activates PrC in vitro, but the reaction is very slow [63]).
However, the main process will take place on the endotheliocyte membrane with the participation of thrombomodulin. It can be assumed that HBO2 will not only stimulate its synthesis in endotheliocytes, but also restore its binding sites on their cytokine-damaged membrane. By suppressing the formation of IL-1 [3], HBO will restore the release of thrombomodulin from endothelial cells, disturbed by this cytokine [63]. If we take into account the ability of HBO2 to cause confor-mational changes in protein molecules [13,64], it is impossible to exclude similar changes in the thrombo-modulin molecule, restoring its affinity for thrombin, which may be disturbed in pathology [51]. The binding of thrombomodulin to thrombin inhibits the procoagulant properties of the latter, thereby increasing the anticoagulant potential of the blood. Meanwhile, when
thrombomodulin interacts with thrombin, conformational changes occur in the latter, turning thrombin into an activator of PrC [51].
It is known that the anticoagulant effect of A-PrS is enhanced by PrS [51]. It can be assumed that the use of HBO in severe SARS-Co-2-associated pneumonia stimulates the synthesis and secretion of PrS into the blood from the liver, as well as its synthesis and accumulation by alpha-granules of platelets (Fig.5). At the same time, the binding of PrS to the C4 protein of the complement system decreases. The free-form pool of PrS formed in the blood in this way and its reserve in platelets create conditions for the long-term preservation of the increased anticoagulant potential of the blood in the posthyperoxic period.
It can be assumed that by stimulating the formation of PrS in endotheliocytes, HBO2 creates conditions for replenishing its reserves with the Golgi complex; at the same time, it restores the deposition on the
periphery of cells (Fig. 5), which is disrupted by prolonged activation of coagulation hemostasis [51]. It was found that by increasing the binding of A-PrS to the en-dothelial cell membrane, PrS creates conditions for the proteolytic inactivation of coagulation factors Va and VIIIa [65]. It can be assumed that HBO not only restores this process, which is disrupted in the severe course of SARS-Co-2-associated pneumonia, but also stimulates it by increasing the PrS as a receptor on the surface of the endothelium of the pulmonary capillaries.
By stimulating the inclusion of thrombomodulin and PrS in the cell membranes against the background of an increase in the concentration of PrS in the blood, HBO2 will increase the profibrinolytic potential of the blood in SARS-Co-2-associated pneumonia. This is due to the ability of A-PrS to inactivate an inhibitor of the plasminogen activator formed in the endothelium [66].
This article substantiates several possible mechanisms of the therapeutic effect of hyperbaric oxygen on the gas exchange function of the lungs in SARS-Co2-associated pneumonia. This is not a truth that must be accepted unconditionally. This is just an attempt to point out the need for a more in-depth study of the mechanisms of the therapeutic effect of HBO in COVID-19.
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