CLINICAL-IMMUNOLOGICAL EFFICIENCY OF OZONE THERAPY IN THE COMPLEX TREATMENT OF PATIENTS WITH PRIMARY OPEN-ANGLE GLAUCOMA

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The relevance of the medical and social problem of glaucoma, as a lifelong disabling disease, increases every year. 

Currently in the world there are 60.5 million patients and 4.5 million blind due to glaucoma, and by 2020 the number of such patients is expected to reach 79.6 million and 11.2 million, respectively [70, 83 , 97].

In Russia, more than 1’mln. patients with glaucoma, over 150 thousand disabled people and more than 66 thousand blind due to glaucoma. The prevalence of the disease is 0.7 per 100 thousand of the adult population. 

Glaucoma ranks first among the causes of disability due to ophthalmic pathology in most regions of Russia [182].

Currently, glaucoma is treated as a progressive multifactorial disease with the development of glaucomatous optic neuropathy (GON) with typical changes in the structure of the optic nerve head (HPN) and the inner layers of the retina [23, 98,]. 

Despite many years of research, many aspects of the etiopathogenesis of the disease remain insufficiently studied, which causes certain difficulties in early diagnosis and makes therapeutic measures ineffective.

In recent years, in the pathogenesis of primary open-angle glaucoma (POAG), great importance is attached to immune inflammation, leading to functional disorders of the organ of vision [55, 78, 114, 157, 159].

One of these mechanisms is a violation of the production of cytokines, which are the main mediators in the autoregulation of the immune response and one of the key markers of the inflammatory process in target tissues where the pathological process develops, including the organ of vision [44, 80, 96, 114].

The data available in the literature on the role of cytokines in this pathology are few and sometimes contradictory [48, 112, 119, 159, 161]. This justifies the relevance of further study of the role of cytokines in the pathogenesis of POAG in order to develop methods to improve the effectiveness of treatment of patients. 

One of these methods is ozone therapy, which is used for various ocular pathologies [15]. A number of researchers have shown that ozone promotes the activation of metabolism, tissue oxygenation, antioxidant system, rate of redox processes, has a detoxification effect, induces the synthesis of cytokines and thereby increases the immunomodulatory properties of the body [56]. 

However, studies on the use of ozone therapy for POAG have not been conducted.

The above substantiates the relevance of further study of the role of immune mechanisms in the pathogenesis of POAG and the development of methods for optimizing the treatment of this pathology.

Purpose of the work: assessment of the clinical and immunological effectiveness of ozone therapy in the complex treatment of patients with POAG.

Research objectives:

1. To investigate the content of pro- and anti-inflammatory cytokines in the blood serum and lacrimal fluid of patients with POAG, taking into account the stage of the glaucomatous process.

2. To investigate the effect of ozone therapy on the dynamics of indicators of the cytokine profile of blood serum and lacrimal fluid of patients.

3. To evaluate the clinical effectiveness of ozone therapy methods in the complex treatment of POAG and to develop indications for its use.

4. Calculate the economic efficiency of ozone therapy in the complex treatment of POAG.

Scientific novelty

According to the results of the study of the cytokine profile of blood serum and lacrimal fluid in patients with POAG, pathogenetically significant correlations between serum and local concentration of cytokines and indicators of the functional state of the organ of vision. 

For the first time in the complex treatment of POAG, ozone therapy was used, the clinical effectiveness of various methods of introducing ozonized physiological solution was assessed, differentiated indications for their appointment were developed, the pharmaco-economic efficiency of the method was calculated. 

The positive effect of ozone therapy on the dynamics of restoration of initially disturbed indicators of the cytokine status of POAG patients was revealed.

The practical significance of the work

On the basis of the results obtained, the diagnostic information content of the study of cytokines in the lacrimal fluid and their relationship with the indicators of visual functions were determined. 

An assessment of the clinical effectiveness of ozone therapy in patients with POAG was carried out, taking into account the stage of the disease, and indications for its use were developed. The pharmaco-economic efficiency of the method is shown in comparison with traditional treatment.

Provisions for Defense

Serum and local concentration of cytokines (TNF-a, IL-1R, IL-8, IFN-y, IL-10, TGFr1) in POAG patients correlates with indicators of the functional state of the visual organ (visual acuity and field of view, critical frequency of flicker fusion, intraocular and true intraocular pressure, coefficient of ease of outflow).

The use of ozone therapy improves the effectiveness of complex treatment of patients with POAG.

Against the background of ozone therapy, there is a faster positive dynamics of serum and local cytokine levels compared to traditional treatment.

The use of ozone therapy in the complex treatment of POAG on the basis of an outpatient clinic provides a significant economic effect.

Personal contribution of the author

The author personally drew up a plan and the main stages of work, analyzed domestic and foreign sources of literature on the topic of the dissertation, selected adequate methods for solving the assigned tasks, personally selected, examined and treated patients, took peripheral blood and tear fluid for laboratory research. 

The author independently carried out the analysis, statistical processing and interpretation of the results obtained, formulated conclusions and practical recommendations. 

The section of the work on calculating the pharmaco-economic efficiency of treatment methods was carried out jointly with the senior lecturer of the Department of Economics and Healthcare Management of Kursk State Medical University, Ph.D. Korshikova T.N.

Approbation of work

The materials of the dissertation were reported and discussed at the interregional scientific-practical conference “Actual issues of ophthalmology” (Voronezh, 2013), interregional scientific-practical conferences “Actual issues of ophthalmology” (Kursk, 2013; Stary Oskol, 2014), 79th All-Russian scientific conference of students and young scientists with international participation “Youth science and modernity” (Kursk, 2014). 

The approbation of the work took place at a joint meeting of the Regional Society of Ophthalmologists, the Department of Clinical Immunology and Allergology and the Department of Ophthalmology of KSMU (Protocol No. 6 of January 11, 2016).

Publications on the topic of the dissertation

Based on the materials of the dissertation, 8 scientific papers were published, including 4 articles in peer-reviewed journals recommended by the Higher Attestation Commission at the Ministry of Education and Science of Russia.

Structure and scope of work

The dissertation consists of an introduction, a literature review, a chapter “Materials and Methods”, the results of their own research, discussion, conclusions, practical recommendations and a list of references. The list of references includes 211 sources, including 139 domestic and 72 foreign. The materials of the thesis are presented on 130 pages of typewritten text and include 13 figures, 20 tables, 2 appendices.

LITERATURE REVIEW

Modern concepts of the etiology and pathogenesis of POAG, the role of immunological mechanisms

Glaucoma is one of the most severe forms of ophthalmopathology, being a lifelong, disabling disease – one of the main causes of blindness and low vision. 

According to statistical studies in the world, there are about 66.5 million patients and 4.5 million blind due to glaucoma [70, 83, 97], and by 2020. the number of such patients is predicted at 79.6 million and 11.2 million, respectively [182].

In Russia, more than 1 million patients with glaucoma, over 150 thousand invalids and more than 66 thousand blind as a result of glaucoma are registered, and among the causes of disability as a result of ophthalmopathology in most regions of Russia, glaucoma ranks first [83, 84, 97].

Currently, glaucoma is considered as a progressive multifactorial disease with the development of glaucomatous optic neuropathy (GON) with typical changes in the structure of the optic nerve head (GL) and the inner retinal layers [23, 35, 36, 98, 157].

It is known that the genesis of the glaucomatous process is characterized not only by an increase in intraocular pressure, but also by the development of specific glaucoma optic neuropathy (GON) [3, 23, 78, 121].

The entire glaucomatous process can be divided into the main pathogenetic stages: impaired outflow of aqueous humor (IV) from the eye, increased intraocular pressure (IOP) above the tolerant level, diffuse or focal ischemia of the optic nerve head, glaucomatous optic neuropathy, atrophy (apoptosis) of retinal ganglion cells [ 9, 10, 23, 94].

Trabeculopathy and scleral sinus blockade are among the main causes of impaired IV outflow [35, 98]. 

With trabeculopathy, a decrease in the number and a decrease in the functional activity of cells in trabeculae was noted; thickening of the trabecular plates; narrowing and partial collapse of the intertrabecular fissures; destruction of fibrous structures; deposition of pigment granules in trabecular structures, exfoliation of glycosaminoglycans. 

The main reasons for the development of trabeculopathy are – early and pronounced age-related involutional processes in trabecular structures; presbyopia, which reduces the activity of the ciliary muscle and is associated in turn with trabecular structures; a decrease in the activity of the antioxidant system and an increase in free radical destructive processes; deterioration of blood supply and hypoxia of the anterior segment of the eye; mechanical deformation of the trabecular filter due to the collapse of the scleral sinus. 

Trabeculopathy impairs the filtering function of the trabecular diaphragm [32, 73, 94, 98].

Scleral sinus blockade results from an increase in the pressure difference between the anterior chamber and the Schlemm canal. At first, the sinus narrows, then in some areas it completely closes. This leads to a decrease in the filtering area and compression of the trabecular apparatus, as a result of which metabolic disorders occur.

In the last decade, great strides have been made towards understanding the mechanisms of the pathogenesis of the disease; numerous factors have been identified that contribute to the development of the glaucomatous process. 

Among them, the leading position is occupied by the biomechanical theory [50, 60, 73, 115, 121], the theory of vascular disorders and vasospasm [2, 7, 8, 152, 180], the genetically determined theory [5, 170, 195, 201], immunological [12, 14, 33, 85, 194, 199].

Taking into account the positions of biomechanics, a modern developing direction in ophthalmology, the state of scleral rigidity (rigidity –

the reciprocal of elasticity) is the main characteristic in the eye, which determines the physiological level of individual intraocular pressure (IOP) and the level of metabolism of eye structures at a given age [60, 73, 15].

To date, a large amount of scientific material has accumulated, indicating changes in scleral tissue with POAG. The work of N.I. Zatulina et al. showed that the initial link in POAG pathogenesis is the increasing disorganization, destruction of the connective tissue of the anterior and posterior segments of the eye [54]. Studies by Iomdina [60], A.N. Zhuravleva [50] revealed the facts of lipoidosis and disfiguring of the inner layers of the sclera, the disappearance of elastic fibers.

The role of the presbyopic factor in the pathogenesis of POAG has been proven [57]. It has been experimentally established that the trabecular apparatus, as presbyopia develops, goes into a state of hypoperfusion and a decrease in permeability [57].

Increased retention of the trabecular meshwork is traditionally considered to be the fundamental pathogenetic link in the development of glaucoma [74, 121]. 

Premature aging of the tissue of the trabecula of the ischlemm canal leads to a decrease in the metabolic activity of these structures, the accumulation of toxic substances and, as a consequence, disruption of their functioning. Diseases such as Alzheimer’s, Parkinson’s, cardiomyopathies, and other storage diseases cause similar changes in target cells [44]. 

These cells are highly differentiated, with a slow mitotic cycle. Nerve tissue and trabecular network fall under these characteristics. 

Aging of trabecular tissue with a cumulative effect of the accumulation of toxic substances leads to a change in the microenvironment of the tissue, an increase in the expression of various pro-inflammatory cytokines, and an increase in the level of active oxygen [51]. 

These processes lead to free radical lipid peroxidation. 

The developing reaction activates synthesis biologically active substances initiating apoptosis [188]. The total number of cells decreases, and the concentration of decay products increases. This, in turn, leads to an increase in resistance and a violation of the hydrodynamics of the eye [47, 65]. 

Studies of trabecular meshwork cells have revealed DNA damage by oxidative processes in patients with glaucoma. When compared with the control group, the number of such cells was significantly higher in the main group. J. Bayerva also showed the most important role of trabecular apoptosis in the pathogenesis of glaucoma [142].

The literature describes changes in the antigenic structure of the tissues of the anterior chamber angle due to involutional processes and vascular disorders associated with aging. Changes in the trabecular tissue and the layers adjacent to the sinus associated with the presence of plasma immunoglobulin-producing cells, less often activated lymphocytes capable of secreting lymphokines, causing spontaneous and antigen-dependent cytotoxicity, were revealed, which is considered as a prerequisite for the development of autoimmune reactions [51, 156].

Currently, more and more works are being published on the relationship between the glaucomatous process and general somatic pathology, in particular, the level of blood pressure. Many authors consider systemic hypotension as one of the reasons for the progression of GON, in particular in normal pressure glaucoma [2, 80]. 

Etiologically, this is due to impaired perfusion in the optic nerve head (OP). In addition, with low arterial pressure, against the background of compensated ophthalmotonus, the vasculature supplying the retina and optic nerve can undergo greater compression, which aggravates the existing tissue ischemia [39, 80, 152]. J. Flamsher pointed out the important role of a comprehensive assessment of not only the state of the organ of vision, but human health in general [52].

Vegetovascular dystonia is also a contributing factor in the development of eye tissue ischemia. 

To standard stimuli at a given pathology, vessels react with vasospasm or vasodilation. In the choroid, the same pathological processes occur, which disrupt the processes of perfusion of the eyeball [41]. M. Emre (2005) established the development of dysfunction of vascular endothelial cells in glaucoma [49]. 

This contributes to an imbalance between vasoconstrictors (endothelin) and vasodilators (nitric oxide). 

In addition, there is a release of biologically active substances with local neurotoxic effects. In support of this theory, the authors recorded a high concentration of endothelin-1 in patients with progressive glaucoma [149]. 

Domestic ophthalmologists have studied the effect of endothelin-1 on eye tissues, as well as correlations between an increase in its level and the presence of migraine in patients with normal pressure glaucoma [88, 89].

The genetic theory of POAG origin is being actively studied. A correlation has been established between the risk of developing glaucoma and a burdened family history [10, 18, 21, 32]. According to M. Shields, a significant proportion of POAG cases is genetically determined and amounts to 21-50%, and the risk of developing this disease among the descendants of glaucoma patients is ten times higher than the average population [106]. 

GON can be inherited according to the Mendelian pattern, in which the disease is caused by the breakdown of only one gene, or non-Mendelian, when glaucoma develops due to a complex series of interactions of genetic material [183]. E. Stone (1997) identified the TIGR gene (trabecularmeshwork induced glucocorticoid response – glucocorticoid-induced trabecular meshwork response), observing a high level of its expression in trabecular meshwork cells after prolonged exposure to dexamethasone [194]. 

In the same year, R. Kubota discovered the expression of the gene in the normal human retina and named it MYOC, and the protein encoded by it, myocilin [170]. 

Currently, more than 25 loci in the genotype have been identified that are responsible for the development of primary open-angle glaucoma [5].

In recent years, more and more attention in the study of the pathogenesis of POAG is paid to immunological aspects. Analysis of the literature has shown that the number of publications devoted to the study of lacrimal fluid is increasing every year [76, 80, 96, 114]. 

To characterize immune disorders, great importance is attached to the study of cytokines, hormone-like mediators of a protein nature, which are produced by cells of the immune system during immunological and inflammatory reactions [7, 8, 44, 80, 96, 114]. 

Cytokines play a central role in the autoregulation of the immune response and its integration with the functions of all body systems (nervous, endocrine, cardiovascular, etc.).

It is of great importance to study not only the systemic production of cytokines, but also their local level in the target tissues, where the pathological process develops.[119].

Immunohistochemical studies have shown that, even in the absence of an inflammatory process, a huge number of cytokines are contained in the tear film of the eyeball [79, 132, 133].

So, in the work of V.V. (2011), studied the composition of the lacrimal fluid in open-angle glaucoma. The analysis of the data obtained revealed an increase in the concentration of TBA-reactive products, reflecting the activation of lipid peroxidation processes, the main pro-inflammatory cytokine IL-1b, and the acute phase protein lactoferrin, which indicates the development of an immune-inflammatory process with damage to the optic nerve and, as a consequence, the progression of visual impairment and blindness. 

In addition, the author found a 5.5-fold increase in the lacrimal fluid of patients with the initial stage of POAG TGF-L2, a cytokine with pronounced proliferative activity and stimulation of fibrosis processes, which is pathogenetically significant during POAG development [136, 138].

In recent years, the attention of researchers has been drawn to the IL-17 family of cytokines, the main producers of which are the CD4 subpopulation lymphocytes – THY7. 

This is due to the importance of their physiological effects and, in particular, protection against auto-aggression. The overproduction of TH7 cytokines (IL-17A, IL-17F, IL-21, IL-22) promotes the induction of autoimmune processes in the body [48, 51, 111].

Few studies presented in domestic and foreign literature indicate that in glaucoma, there is a high level of IL-17 in the lacrimal fluid [12, 45, 134]. It is known that a high concentration of IL-17 negatively affects the function of the main cells of the extracellular matrix of the structure of the optic nerve disc and surrounding tissues, in particular astrocytes, accelerating their death and degradation.

 It was found that in patients with POAG, the concentration of the studied cytokine in the lacrimal fluid was 4-5 times higher than in the control group. It was found that the degree of expression of IL-17 was directly related to the progression of glaucomatous lesions [114]. 

Based on the study, it was concluded that in this regard, a number of authors in their works recommend the study of IL-17 in the tear fluid for non-invasive diagnosis of the early stage of POAG [131].

Along with this, the literature provides data on the participation in the pathogenesis of POAG of the regulatory cytokine interferon-gamma (SB-y), which is an activator of macrophages in the development of destructive processes in the inflammation focus [13, 55, 196]. 

In a number of studies in the study of serum and local levels of SB-y, an increase in the content of this cytokine in all patients with POAG was noted by 2 times compared with those in healthy individuals. In the initial and advanced stages, in contrast to the far advanced and terminal stages of POAG, the production of SB-y is more pronounced [132, 133]. The authors found that the hypersecretion of FN-y indicates the activation of the T-cell link immunity, especially in the earlier stages of the disease and in patients at risk of developing glaucoma [112, 189, 198].

The most significant and studied role in the pathogenesis of glaucoma and other types of ophthalmopathology is the role of cytokines such as tumor necrosis factor alpha (TNF-a) and transforming growth factor beta-1 (TGF-P1).

Proinflammatory cytokines, in particular TNF-a, play a special role in the induction of vascular damage. This cytokine is synthesized mainly by cells of the monocyte-macrophage series. TNF-a enhances the expression of adhesion molecules, increases the functional activity of cells responsible for the development of inflammation, and stimulates the procoagulant activity of the endothelium. Also, proinflammatory cytokines can disrupt lipoprotein metabolism and enhance the processes of lipid peroxidation in the vascular wall [25, 43, 62, 65].

Filed under WeinF.B., Beut.L. (2002) the concentration of TNF-a in the retina and optic disc correlates with the rate of death of ganglion cells in GON [207]. In addition, it is assumed that under the influence of TNF-a, glial cells grow, and this leads to an increase in hydrostatic pressure and ischemia in cell cultures.

 On the other hand, there is evidence that TNF-a has a neuroprotective function. Its intravitreal administration promoted the survival of retinal ganglion cells [141]. 

An increase in the amount of TNF-a activates the secretion of metalloproteinases, which play an important role in tissue remodeling, angiogenesis, proliferation, migration and differentiation of cells, apoptosis, suppression of tumor growth, cleavage of membrane receptors, release of apoptotic ligands such as TNF-a, as well as in the activation and deactivation of chemokines and cytokines [165].

The progression of many types of ophthalmopathology is facilitated by the increased production of a number of growth factors, in particular TGF-P1, which is by its nature an anti-inflammatory cytokine. Its anti-inflammatory effect is manifested by suppression of secretion proinflammatory cytokines and thus regulation of the severity of tissue damage [25, 65].

The activation of endothelial cells by cytokines increases the synthesis of TGF-pi, which has a strong anti-inflammatory effect on vascular cells. Several prospective studies have shown that TGF-pi inhibits the production of IL-8 and TNF-a by activated endothelial cells, and also inhibits IL-8-dependent migration of neutrophils across the activated endothelial layer. 

These studies have also shown that TGF-pi prevents TNF-a-induced impairment of vasodilation [147, 175, 201].

Most of the anti-inflammatory effects of TGF-pi in vascular cells have been studied in vitro in mice. TGF-pi-deficient mice died in the perinatal period from multiple large, uncontrolled foci of inflammation. 

These results clearly show that the presence of endogenous TGF-pi inhibits inflammation in the vascular wall [154, 169]. It is assumed that TGF-pi plays a significant role in the processes of vascular wall remodeling mainly due to the processes of inhibition of migration and proliferation of endothelial cells and cells of the monocytic-macrophage series [169, 192]. At the same time, the role of TFR-pi in this process is ambiguous.

In a number of studies, it has been shown that, in the case of overproduction, this cytokine, in addition to protective and antiproliferative ones, can also exhibit angiogenic properties [173, 192]. In addition to regulating the processes of cell proliferation, differentiation, and apoptosis, this cytokine stimulates the production of the extracellular matrix and proteoglycans that are part of the connective tissue [197, 199].

Thus, by exerting a pronounced anti-inflammatory effect, TGF-pi impairs the processes of vascular wall remodeling [169]. A number of researchers have shown that with hyperproduction, this cytokine, in addition to

protective and antiproliferative, may also exhibit angiogenic properties [65, 173, 192]. It should be noted that, according to the literature, this cytokine is detected in the lacrimal fluid in 100% of cases [43, 100].

Questions about the possibility of the participation of immune processes in the development of GON in connection with the increased content of pro-inflammatory cytokines in the composition of the lacrimal fluid are discussed.

 The level of IL-1R and IL-8 in the lacrimal fluid and blood serum is being actively studied [162, 171, 179] ..

According to a number of researchers, the level of IL-1P in patients with POAG is increased tenfold [12, 20, 119, 124, 174]. 

It was revealed that the increase in IL-1R and IL-8 in the lacrimal fluid and blood serum is probably associated with infection; the importance of such infectious agents as Chlamidia trachomatis, Mycoplasma pneumonia, Mycoplasma hominis is not excluded [203].

 There is an opinion that the increase in IL-1P in the lacrimal fluid in various eye diseases does not correlate with the type of disease, the size of the defect and the depth of the lesion, but depends on the lesion of the limbal region [162].

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