OXYGEN-DEPENDENT MECHANISMS OF PHYSIOLOGICAL ACTION OF OZONE

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The analysis of literature and own data on the study of the mechanisms of the physiological effect of ozone on the body has been carried out.

With the introduction of this gas, activation of metabolism is observed, blood circulation and oxygen delivery to ischemic tissues are improved.

Ozone is able to shift the redox balance of metabolic systems and cause compensatory mobilization of endogenous antioxidants from the depot, activate the enzymatic link of antiradical defense; these effects are aimed at stabilizing the dynamic balance between free radical lipid oxidation and antioxidant processes in the body.

The influence of this physical factor on the oxygen transport function of blood is considered.

Ozone changes the functional properties of hemoglobin – in particular, through the pathway “hydrogen sulfide – cysteine ​​– cystine” and NO-ergic mechanisms.

The increase in the concentration of nitrogen monoxide in the blood is associated with the ability of ozone to activate factors that facilitate the expression of NO synthase.

The interaction of nitrogen monoxide and hydrogen sulfide can affect the modification of the affinity of hemoglobin for oxygen through the formation of various hemoglobin derivatives, modulation of the intra-erythrocyte system for the formation of the oxygen-binding properties of blood, as well as through the systemic mechanisms of the formation of the functional properties of hemoglobin.

The effect of ozone is manifested in an increase in the content of such gas transmitters as nitrogen monoxide and hydrogen sulfide, which affects the modification of the oxygen-binding properties of blood.

The anti-hypoxic effect of this gas is realized with the participation of intra-erythrocyte gas transmission mechanisms, which justifies the possibility of its use in medical practice.

The established regularities concretize the effects of ozone and can be used as a theoretical basis for the development of new ways to improve the body’s adaptive capabilities during hypoxia.

The use of ozone (O3) in medicine for solving problems of practical health care (treatment and rehabilitation of the human body) is one of the most dynamically developing areas of physiotherapy [1].

Ozone therapy is actively used both in clinical and preventive medicine, belongs to the group of methods of oxidative therapy, which includes both well-known (hyperbaric oxygenation, ultraviolet blood irradiation, low-intensity laser radiation, etc.), and new methods (use of nitric oxide donors, singlet oxygen therapy).

One of the most promising methods of influence may be the use of O3 in oncological practice [2].

Incubation of adenocarcinoma cells in a medium with O3 reduces their viability [3].

The use of an ozone-oxygen mixture (5 ml, at an O3 concentration of 40 μg / ml, for 4 weeks) in patients with glioblastoma in the postoperative period in combination with radio-chemotherapy increases their lifespan [4].

Ozone (at a concentration of 1.2–1.5 mg / ml) has a decongestant effect, reduces the level of endogenous intoxication, improves the delivery and utilization of oxygen by tissues, and activates the process of aerobic oxidation in the complex of postoperative treatment in patients with neoplasms of the head. brain [5].

In complex treatment, O3 stimulates cell proliferation, has a wound healing effect [6].

This factor affects microorganisms and viruses, destroying their capsules and damaging deoxyribonucleic and ribonucleic acids [7].

Ozone-oxygen mixture injection (80 μmol / kg, at a concentration O3 50 μg / ml) in mice infected with the virus papillomas HPV16, lead to a decrease in dysplastic skin lesions [8].

The use of ozone therapy in patients with acute pyelonephritis leads to a decrease in endo-toxicosis and activation of antioxidant mechanisms [9].

The use of O3 (at a concentration of 3-4 μg / ml per 400 ml, twice a day, intravenously drip) increases the effectiveness of therapeutic measures in acute pancreatitis, reducing the number of complications [10].

Intraperitoneal administration of O3 to rats with osteomyelitis of the femur increases the antioxidant activity, decreases the inflammatory response, necrosis, and edema [11].

Due to its high reactogenic ability, O3 actively enters into reactions with various biological objects, the main target of its physiological action is the membrane structures of the cell.

With the introduction of even low doses of this gas, the activation of metabolism is observed, accompanied by an increase in the content of free and dissolved oxygen (O2) in the blood [12].

Ozone improves blood circulation and delivery of adenocarcinoma cells in an environment with O3, reduces oxygen supply to ischemic tissues, and also increases the level of 2,3-diphosphoglycerate (2,3-DPG), enhances general metabolism, and ensures good health in most patients, activates neuroprotective systems [13].

Ozone therapy provides enhanced oxygen delivery to insufficiently vascularized tissues, which is confirmed by blood gas analysis (oxygen tension (pO2) in venous blood after a course of ozone therapy decreases from 40 to 20 mm Hg); improved metabolism in tissues, it neutralizes the negative effects of hypoxemia, in which OH– ions are formed in excess, changing, in particular, the functions of interleukin-1 [14].

When using [17].

It is important to note the positive effect of this gas on microcirculation due to the activation of NO synthase, which is a powerful vasodilator [18].

Ozone, depending on the dose and methods of administration, is able to shift the redox equilibrium of metabolic systems and cause compensatory mobilization of endogenous antioxidants from the depot, activate the enzymatic link of antiradical defense; these effects are aimed at stabilizing the dynamic balance between free radical oxidation of lipids and antioxidant processes in the body [14].

The shift in the redox balance of the organism, which occurs as a result of the action of O3, leads to the accumulation of oxidized glutathione and, consequently, to the activation of the glucose phosphate shunt: an increase in the level of glucose-6-phosphate dehydrogenase, accumulation of reduced nicotinamide-adenine dinucleotide [19].

Using this method, the ability to quickly return oxyhemoglobin oxygen decreases very slowly – over several weeks and even months, prolonging the therapeutic action О3 [15].

The effect of an ozone-oxygen mixture with an O3 concentration of 10–100 μg / l on the blood of dogs causes a pronounced increase in the pO2 level [16].

It was found that the incubation of O3 in the dose range of 1–3 mg / L with erythrocyte mass leads to an increase in the content of adenosine triphosphate (ATP) and 2,3-DPG, while high concentrations of O3 (5–11 mg / L) do not have such effect [17]. It is important to note the positive effect of this gas on microcirculation due to the activation of NO synthase, which is a powerful vasodilator [18].

Ozone, depending on the dose and methods of administration, is able to shift the redox equilibrium of metabolic systems and cause compensatory mobilization of endogenous antioxidants from the depot, activate the enzymatic link of antiradical defense; these effects are aimed at stabilizing the dynamic balance between free radical oxidation of lipids and antioxidant processes in the body [14].

Redox shift balance of the organism, which occurs as a result of the action of O3, leads to the accumulation of oxidized glutathione and, consequently, to the activation of the glucose-phosphate shunt: an increase in the level of glucose-6-phosphate dehydrogenase, accumulation of reduced nicotinamide-adenine dinucleotide [19].

[17]. It is important to note the positive effect of this gas on microcirculation due to the activation of NO synthase, which is a powerful vasodilator [18].

Ozone, depending on the dose and methods of administration, is able to shift the redox equilibrium of metabolic systems and cause compensatory mobilization of endogenous antioxidants from the depot, activate the enzymatic link of antiradical defense; these effects are aimed at stabilizing the dynamic balance between free radical oxidation of lipids and antioxidant processes in the body [14].

The shift in the redox balance of the organism, which occurs as a result of the action of O3, leads to the accumulation of oxidized glutathione and, consequently, to the activation of the glucose phosphate shunt: an increase in the level of glucose-6-phosphate dehydrogenase, accumulation of reduced nicotinamide-adenine dinucleotide [19].

Numerous studies have shown that correction of chronic oxidative stress O3 by increasing the level of antioxidant enzymes leads to an increase in erythroblast differentiation; in addition, O3 increases the level of prostacyclin, a known vasodilator [20]. An increase in the concentration of

nitrogen monoxide (NO) under the influence of O3, possibly related to its ability to activate factors that facilitate the expression of NO synthase; Moreover, stimulation of O3 in the production of antioxidant enzymes also suggests an increase in NO levels. Oxidation processes caused by the use of O3 in renal ischemia-reperfusion syndrome lead to an increase in the concentration and inducible expression of endothelial NO synthase, which indicates a close relationship of oxidation processes with an increase in NO production, and also helps to reduce damage kidney by reducing the production of endothelin [18].

With long-term use of O3 in high doses (2.0 and 8.0 μg), it has an inhibitory effect on lipid peroxidation (LPO) and the general antioxidant status of blood, increasing the activity of superoxide dismutase, and at a dose of 0.6 μg – less pronounced toxic effect [21].

We found that the action of O3 at concentrations of 2, 6, 10 mg / l leads to an increase in the activity of free radical blood processes, manifested by an increase in the levels of malondialdehyde (MDA) and dienic conjugates (DC) in the erythrocyte mass, and also an increase in catalase activity, the content of alpha-tocopherol and retinol.

The most pronounced growth of the above parameters is observed at O3 concentrations of 6 and 10 mg / l [22].

Therapy performed in elderly patients with ischemic heart disease with stable exertional angina of functional class I-II, in the form of intravenous drip administration of ozonized saline solution with O3 concentration 2-4 mg / l (3 times a week against the background taking one of three drugs: nitrates, beta-blockers, or angiotensin-converting inhibitors

the enzyme) provides a stable and uniform antihypertensive effect, reducing the average daily level of systolic and diastolic blood pressure and slowing down the heart rate [23].

The main targets for intravenous administration of O3 are cell membranes of blood corpuscles (lymphocytes, erythrocytes, platelets), vascular wall cells, and plasma metabolites. When O3 interacts with bioorganic substrates, primary ozonide is formed, which is unstable and decomposes to form

a carboxyl compound and a carbonyl oxide; interacting, the latter form secondary ozonide, which decomposes upon reduction with the formation of peroxide, which is the strongest oxidizing agent [24].

A small amount of O3 peroxides greatly increases oxygen consumption by the blood; in addition, 2,3-DPG is formed in erythrocytes, which determines the bond strength hemoglobin with oxygen, facilitating its release, and improves oxygen supply to tissues [21].

The effect of this gas on platelets is to reduce their ability to aggregate due to changes in the structure of the cell membrane and its charge [25].

Ozone activates the work of the enzyme Na + / K + -ATP-ase, as a result of which the entry of potassium into cells and the release of sodium ions increase, which prevents the adhesion of erythrocytes and their adhesion to the vascular wall [26]. The activation of fibrinolytic activity and a decrease in the level of fibrinogen in the blood are shown

when exposed to O3 [27]. Ozone-effects on the cellular composition of the blood – erythrocytes, platelets, leukocytes, endothelial cells

and their intracellular components – form a multifactorial, optimally coordinated metabolic cellular response, maintaining a high immune status of cells in a highly toxic environment of the body [28]. This factor stimulates the proliferation of immunocompetent cells and the synthesis of immunoglobulins. In guinea pigs placed in a chamber with ozone, an increase in mature eosinophils is noted [29].

When examining patients with a sub-compensated form of chronic placental insufficiency, who received ozonized isotonic sodium chloride solution daily for 5-7 days, significant positive shifts were revealed (in 83.3% of cases), manifested in normalization altered parameters of hemostasis, immunity, LPO and antioxidant defense system [30].

The introduction of ozonized isotonic sodium chloride solution (200 ml, with an O3 concentration of 400 μg / l) to pregnant women with iron deficiency anemia demonstrated its high efficiency due to anti-hypoxic properties, which consist in increased oxygen release to insufficiently blood-supplied tissues, improvement tissue respiration and normalization of the rheological properties of blood, which made it possible to reduce the duration of therapy for patients [31].

The use of O3 demonstrates a wide variability of its effects, which may be due to the peculiarity of the implementation of the effect of this gas, the difference in doses and conditions in which it is introduced.

The activation of the body’s metabolism is observed even with the introduction of very low doses of O3: an increase in the content of free and dissolved oxygen in the blood, an intensification of the activity of enzymes that catalyze aerobic oxidation of carbohydrates, lipids and proteins with the formation of the energy substrate ATP [32].

Ozone has a pronounced anti-hypoxic effect, which is explained by an improvement in the rheological properties of blood, an increase in the release of oxygen by oxyhemoglobin to tissues and an increase in the rate of microcirculation.

A session of ozone therapy leads to an improvement in blood rheology in patients with complex pathology not only immediately after the procedures, but also within two months after the course, which is due to a decrease in the micro-viscosity of membranes, the strength of aggregates and the rate of spontaneous aggregation of erythrocytes, an increase in their deformability [33 ].

In the body, the affinity of hemoglobin for oxygen (SGA) largely determines the diffusion of oxygen from the alveolar air into the blood, and then, at the capillary level, into the tissue [34].

The shift of the oxyhemoglobin dissociation curve (KDO) to the right is aimed at compensating for oxygen deficiency, and under conditions of oxidative stress, when oxygen utilization by tissues is impaired, it affects the activity of free radical oxidation processes.

There are isolated works on the direct effect of O3 on the SGC. Thus, the effect of O3 (1–3 ‰) on the blood did not affect the delivery of oxygen, including the SGC and the concentration of 2,3-DPG in erythrocytes [35].

However, in a study of patients with peripheral arterial occlusion, ozonized auto-hemo-transfusion (reinfusion of 100 ml of autologous blood previously exposed to O3 for 10 min) increased the p50 std value (partial pressure of oxygen in the blood at which hemoglobin is saturated with oxygen 50% under standard conditions), while the level of 2,3-DPG did not change significantly [36].

The use of O3 (at concentrations of 6.5; 13; 26; 78 μg / l) in in vitro experiments with blood taken from patients with vascular obliterating atherosclerosis (stages II – IV according to Fontane’s classification) and diabetes mellitus of the second type, led to a decrease in SGC[37].

The use of O3 for blood loss in rats causes an increase in the activity of Na + / K + -ATPase, due to the development of compensatory processes due to an increase in the concentration of 2,3-DPG, which decreases FGC, and also due to a decrease in the concentration of ATP [38].

As a result of ozonolysis, a cascade of reactions is induced, which ultimately lead to an increase in the level of 2,3-DPG, facilitating the release of oxygen from oxyhemoglobin [39].

2,3-DPG is an important factor in the intra-erythrocyte system of regulation of the oxygen-binding properties of the blood, which ensures its adaptive changes.

According to our data, incubation of blood with ozonized saline solution in the range of O3 concentrations in solution from 2 to 10 mg / L at exposure of 30 and 60 min causes a change in the oxygen transport function of the blood, which manifests itself in an increase in oxygen tension, the degree of oxygenation and a decrease in CGC. ; the severity of these changes increases with an increase in the concentration of O3 [40].

It can be assumed that the positive clinical effect of ozone therapy noted in a number of works [41] is due, as was observed in our experiments, to a shift of the EDC to the right, which improves the oxygen flow in the tissue.

Physiological activity of O3 in the body is the result of a change in the free radical status in response to the intake of active oxygen and ozone metabolites from an external source [42].

It is known that the addition of 0.4 ml of ozonized isotonic solution sodium chloride with a concentration of O3 400, 800, 1200 μg / l to the blood of pregnant women with a threat of miscarriage causes an increase in the content of both primary and final LPO products (the level of DC in the blood becomes 2.4 times higher than in healthy pregnant women) [43].

When exposed ozone-oxygen mixture with an O3 concentration of 10–100 μg / L for the blood of dogs, it was found that the minimum O3 concentrations (10 and 20 μg / L) do not cause a shift in lipid peroxidation relative to the initial equilibrium state, and at at higher doses of O3 (starting from a concentration of 50 μg / L), the intensity of the formation of the end products of lipid peroxidation increases [16].

When rats are injected with washed erythrocytes and an ozonized isotonic solution of 0.9% NaCl (2 ml, with an O3 concentration of 2 mg / l) after blood loss, the MDA content increases by 15%, an increase in the activity of antioxidant enzymes is observed in tissues and organs: superoxide dismutase, catalase, and glutathione peroxidase [17].

Intravenous infusion of ozonized saline solution (6 procedures through day, at an O3 concentration of 2.2–2.4 mg / l) in patients with myasthenia gravis lead to a decrease in the activity of free radical processes [44].

In response to the introduction of the first doses of O3, a slight increase in free radical processes is observed, and with further addition of this gas in tissues and organs, an increase occurs, first of all, the activity of antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase), indicating activation of the body’s antioxidant system [45], this was also observed in our experiments.

In addition, O3 affects the oxygen-dependent processes of the body: it is able to stimulate the energy by optimizing the utilization of oxygen and energy substrates in energy-producing systems, to increase the energy efficiency of tissue oxidative processes, when exposed to it, an increase in the activity of enzymes that catalyze aerobic oxidation of carbohydrates, lipids and proteins with the formation of an energy substrate ATP is noted.

It can be assumed that the shift of the DRC to the right contributes to the improvement of the oxygen flow in the tissue, and under conditions of oxidative stress, when oxygen utilization by the tissues is impaired, it affects the activity of free radical oxidation processes.

[46]. The revealed O3 effect on SGC is realized as directly through the contribution to the functioning of the “cysteine-cystine” systems and “L-arginine-NO”, and through the modification of the functional properties of hemoglobin.

The NO gas transmitter is an allosteric effector of SGC: incubation of blood with the NO donor (nitrosocysteine) leads to a left-sided shift in EDV.

Gas transmitters are a class of physiologically active substances that perform a signaling function in cells and are involved in intercellular and intracellular communication. Interaction

The presence of NO and hydrogen sulfide (H2S) can affect the modification of SGC through the formation of various derivatives of hemoglobin, modulation of the intra-erythrocyte system of the formation of oxygen-binding properties of the blood, and also, indirectly, through the systemic mechanisms of formation of the functional properties of hemoglobin.

We have found that the O3 effect is manifested in an increase in the content of such gas transmitters as NO and H2S, which is important for the modification of the oxygen-binding properties of blood.

The greatest increase in the level of these gas transmitters is noted at an ozone concentration of 10 mg / l [47].

The observed antihypoxic effect of O3 is realized with the participation of gas transmitters and intra-erythrocyte mechanisms that change the oxygen transport function of the blood (see figure).

Thus, the analysis of the scientific literature and our own data on the study of the mechanisms of the physiological effect of O3 on the body indicates that the anti-hypoxic effect is realized through systems that change the oxygen transport function of the blood.

Ozone therapy can be used to improve adaptation mechanisms during hypoxia.

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