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1652 East European Scientific Journal #1(65), 2021 эмоциональной неустойчивости. Высокий уровень тревожности и боязни наблюдается у 86,7 % курсантов. У 26,1% из них выявлен высокий уровень неуверенности в себе, что может непосредственно сказываться на уровне ситуативной и личной тревожности. У 34,8 % опрошенных курсантов выявлен средний уровень неуверенности в себе и только 39,1% опрошенных курсантов не имели проблем с самооценкой.
Заключение
Таким образом, по результатам проведенного исследования, социально-гигиенический «портрет» курсанта характеризуется высоким уровнем распространенности кариеса зубов и хронического гингивита на фоне «плохого» уровня гигиены полости рта. На основе анкетирования установлено, что наиболее значимыми факторами оказались низкая медицинская активность, наличие стрессовых ситуаций и нервно-психического напряжения во время учебы УЮИ МВД РФ по РБ. Следовательно, для лечения и профилактики стоматологических заболеваний у курсантов в период адаптации к условиям обучения и проживания в казарме, когда не выявлено преобладание нарушения либо миогенной, либо нейрогенной регуляции может быть рекомендовано использование ультрафиолетового облучения с использованием альвожила в десневые карманы, которые дал прекрасные результаты.
Конфликт интересов. Авторы декларируют отсутствие явных и потенциальных конфликтов интересов, связанных с публикацией настоящей статьи.
Источник финансирования. Авторы заявляют о финансировании проведенного исследования из собственных средств
Литература
1. Агаджанян Н. А. Проблемы адаптации и учение о здоровье: учеб. пособие/ Н. А. Агаджанян, Р. М. Баевский, А. П. Берсенева. М.: Издво РУДН, 2006. [Agadzhanyan N. A. Problemy adaptacii i uchenie o zdorov'e: ucheb. posobie/ N. A. Agadzhanyan, R. M. Baevskij, A. P. Berseneva. Moscow: Izdvo RUDN, 2006. (In Russ.)]
2. Castillo DM, Sanchez-Beltran МС, Castellanos JE, Sanz I, Mayorda-Fayad I, Sanz M, Lafaurie GI. Detection of specific periodontal microorganisms from bacteriemia samples after periodontal therapy using molecular-based diagnostics. J. Clin. Periodontol. 2011;38:418-427.
3. Гажва С.И., Гулуев Р.С. Распространенность и интенсивность воспалительных заболеваний пародонта (обзор литературы). Обозрение. Стоматология. 2012;1:13-14. [Gazhva S.I., Guluyev R.S. The prevalence and intensity of inflammatory periodontal diseases (literature review). Review Dentistry 2012;1:13-14 (In Russ.)]
4. Keshava PK, Sangeeta NU. Stressing the stress in periodontal disease. J. Pharm. Biomed. Sci. 2013;26:345-348.
5. Debnath M. Recent advances in psychoneuroimmunology: Inflammation in psychiatric disordes. Translat. Neurosci. 2011;2(2):121-137.
6. Akcali A, Huck О, Tenenbaum Н, Davideau JL, Buduneli N. Periodontal diseases and stress: a brief review. J. Oral. Rehabil. 2013;40(1);60-68.
7. Teles, FR, Tele RF, Uzel NG et al. Early microbial succession in redeveloping dental biofilms in periodontal health and disease. J Periodontal Res. 2012;47(1):95-104.
UDC:616.314.17-008.1-092.12 ГРНТИ: 76.01.11
Yarov Yu.Yu.
Doctor of philosophy, assistant of the department of dentistry, Donetsk National Medical University, Ukraine
Turchenenko S.O. assistant of the department of dentistry, Donetsk National Medical University, Ukraine
Reva O.P.
student of the department of dentistry, Donetsk National Medical University, Ukraine
MODERN VIEWS ON LEADING FACTORS IN THE ORIGIN AND DEVELOPMENT OF
GENERALIZED PERIODONTITIS
Яров Ю.Ю.
Доктор философии, ассистент кафедры стоматологии, Донецкий национальный медицинский университет, Украина
Турчененко С.О. ассистент кафедры стоматологии, Донецкий национальный медицинский университет, Украина
Рева О.П.
студентка стоматологического факультета, Донецкий национальный медицинский университет, Украина
СУЧАСН1 УЯВЛЕННЯ ПРО ПРОВ1ДН1 ЧИННИКИ У ВИНИКНЕНН1 ТА РОЗВИТКУ ГЕНЕРАЛ1ЗОВАНОГО ПАРОДОНТИТУ
Summary: The development of generalized periodontitis is preconditioned by two groups of factors - local and general. Local factors include the influence of the microflora of the dental biofilm on the background of changes in the local immunity of the oral cavity, anatomical and topographic features of the oral cavity, masticatory dysfunction due to abnormal jaw development, traumatic occlusion and early tooth loss. Common factors include stress, psycho-emotional stress, ionizing radiation, insufficient alimentary intake of vitamins, macro- and microelements, concomitant pathology of internal organs, endocrine and genetic disorders. In response to prolonged microbial persistence, an inflammatory process develops in the periodontal tissues, which is the complex of microcirculatory, hematological, immunological and connective tissue reactions to damage. Disruption of microcirculation provokes tissue hypoxia, activation of free radical oxidation, disorganization of biofilms with the release of physiologically active substances (prostaglandins, cytokines). The nature and rate of development, intensity and prevalence of the inflammatory process in periodontal tissues are determined by intercellular and intersystem interaction with the participation of different populations of leukocytes and substances produced by them. The leading role in the resorption of alveolar bone belongs to pro-inflammatory cytokines, prostaglandin E2 and the system of regulatory proteins RANKL-RANK-OPG, which determines the pathways of drug correction of alveolar bone remodeling. The level of the corresponding inflammatory reaction to damage is determined by the reactivity of the organism. The issues of clarifying the key mechanisms of the inflammatory process in periodontal tissues depending on the initial state of reactivity of the organism remain relevant, which determines the feasibility of further research.
Аннотация: Развитие генерализованного пародонтита обуславливается двумя группами факторов -локальными и общими. К местным факторам относят - влияние микрофлоры дентальной биопленки на фоне изменения состояния местного иммунитета полости рта, анатомо-топографические особенности ротовой полости, нарушения жевательной функции вследствие аномалий развития челюстей, травматической окклюзии и ранней потери зубов. К общим факторам относятся - стресс, психоэмоциональное напряжение, ионизирующая радиация, недостаточное алиментарное проступление в организм витаминов, макро- и микроэлементов, сопутствующая патология внутренних органов, эндокринные та генетические расстройства. В ответ на длительную микробную персистенцию развивается воспалительный процесс в тканях пародонта, который представляет собой комплекс микроциркуляторных, гематологических, иммунологических и соединительнотканных реакций на повреждение. Нарушение микроциркуляции инициирует тканевую гипоксию, активацию свободнорадикального окисления, дезорганизацию биологических мембран с высвобождением физиологически активных веществ (простагландинов, цитокинов). Характер и скорость развития, интенсивность и распространенность воспалительного процесса в тканях пародонта определяются межклеточным и межсистемным взаимодействием при участии разных популяций лейкоцитов и продуцируемых ими веществ. Ведущая роль в резорбции альвеолярной кости принадлежит провоспалительным цитокинам, простагландину Е2 и системы регуляторных белков RANKL-RANK-OPG, что определяет пути медикаментозной коррекции ремоделирования альвеолярной кости. Уровень ответной воспалительной реакции на повреждение определяетсяся реактивностью организма. Актуальными остаются вопросы уточнения ключевых механизмов течения воспалительного процесса в тканях пародонта в зависимости от исходного состояния реактивности организма, что обуславливает целесообразность дальнейших исследований.
Key words: generalized periodontitis, risk factors, nature of inflammation, reactivity of the organism.
Ключевые слова: генерализованный пародонтит, факторы риска, характер воспаления, реактивность организма.
Mass spread, the significant increase in destructive forms at the young age, high percentage of recurrences confirm the fact that among the current problems of modern dentistry, generalized periodontitis (GP) occupies one of the leading places. Numerous data from the literature suggest that the development of generalized periodontitis happens due to two groups of factors - local and general ones. Local factors include the influence of opportunistic and specific periodontopathogenic microflora of the dental biofilm against the changes in the local immunity of the oral cavity, anatomical and topographic features of the oral
cavity (shallow dorsum, anomalies of attachment of bridles of the lips, tongue), masticatory disorders due to traumatic occlusion and early tooth loss, etc. [1]. General factors include emotional stress and chronic psycho-emotional stress, ionizing radiation, insufficient nutritional intake of vitamins, macro-and micronutrients, concomitant pathology of internal organs, endocrine disorders, etc. [2]. At the early stages, the pathological process in the periodontal tissues takes the form of classic acute exudative inflammation with the combination of alteration, exudation and proliferation. No reparation of damaged
54 East European Scientific Journal #1(65), 2021 tissues and restoration of homeostasis can be observed, as the process acquires signs of chronic inflammation due to prolonged and constant persistence of the harmful factor (periodontopathogenic microflora) and the development in this regard the dysfunction of immune system and corresponding morphological changes in tissues, which ultimately leads to irreversible destruction of the periodontium and alveolar bone [3]. Thus, in cases of periodontitis, inflammation loses its biological feasibility as a protective and adaptive response of the organism, as it loses the ability to destroy and eliminate the damaging factor. In periodontal tissues, complex and multicomponent processes - inflammation and destruction - take place in parallel and continuously. The outcome of the disease is largely determined by the compensatory abilities of the protective mechanisms of the periodontium and the body in the whole.
Most researchers consider the influence of dental biofilm to be of crucial importance in the development of inflammatory changes in the periodontium [4]. This is confirmed by numerous data from clinical, epidemiological, microbiological and immunological studies. According to various authors, 1 mg of plaque contains from 5 to 800 million microorganisms. Modern methods of identifying microflora have made it possible to detect about 500 species of various bacteria from the gingival sulcus only. Along with the bacterial flora in the biofilm there are also representatives of yeast-like fungi, protozoa, viruses. The study of the rate of plaque formation during its maturation (1-9 days) has shown that it is most intensely formed on the first day, on the following days the rate of its deposition is significantly reduced. For the first 3-4 hours, the highest rate of plaque formation can be observed. The convincing proof of the role of dental biofilm in the development of the inflammatory process was the experiment conducted on 11 Chinese students who did not have any dental and periodontal disease [5]. The results of bacteriological studies showed that on the 14th day of the experiment cocci (mainly streptococci) and rods (mainly actinomycetes) dominated in the dental biofilm. Till the end of the experiment, in process of development of gingivitis in plaque the proportion of gram-negative cocci and rods (mainly fusobacteria and capnocytophages) increased. Thus, the studies have shown the significant role of oral hygiene in the development of inflammatory periodontal disease.
Earlier scientists believed that pathological changes in periodontal tissues occured when the number of dental plaque microorganisms (up to "critical mass") in the gingival sulcus increased sharply, and the protective mechanisms of the oral cavity and periodontal tissues were no longer able to resist microbial aggression. At the same time any specific activators were not allocated, and all saprophytic and conditionally pathogenic microflora of the dental plaque was considered as the trigger for development of inflammation and destruction of periodontal tissues. Since 1984, the leading scientists in the field of periodontal microbiology S.S Sokransky
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and A.D Haffaji (Boston Dental Center, USA), have developed and further confirmed the concept of specific periodontal pathogenic microflora, i.e. specific bacteria of the dental biofilm, which due to the presence of special virulence factors are able to overcome numerous protective barriers and have a detrimental effect on vapor tissues. [6]. Currently, there are from 8 to 12 species of specific periodontal pathogenic bacteria. These are mainly representatives of facultative and obligate anaerobes, such as Porphyromonas gingivalis, Actinobacillas actinomicetemcomitans, Treponema denticola, Prevotella intermedia, Fusobacterium nucleatum, Capnocytophaga spp., Campilobacter etc. Most of these microorganisms are permanent commensals of the oral cavity, i.e. found in the dental plaque of people, regardless of whether they have periodontal disease or not, and only a few of them, including Treponema denticola, are transient microorganisms that can enter the oral cavity from other related areas (gastrointestinal tract, nasal cavity). The basis for the selection of these microorganisms in the group of potential periodontal pathogens were experimental studies on the model of periodontitis in animals and numerous clinical studies in patients with different variants of periodontitis, confirming the presence of the largest number of bacteria in active inflammation and destruction of periodontal tissues and the highest titer of antibodies to them in gingival and oral fluid and blood serum [7]. We believe that not only the qualitative composition of the biofilm (namely periodontal pathogens) is the cause of inflammatory periodontal disease, but their quantitative relationship with the probiotic microflora is important, which has been confirmed in our study [8]. Thus, the analysis of current literature data emphasizes the role of microbial factors as being a trigger for the development of inflammation and immunopathological reactions in the periodontium. In response to the long-term persistence of periodontopathogenic microflora, in accordance with the general principles of chronic inflammation, the inflammatory process develops in periodontal tissues, which is a complex of microcirculatory, hematological, immunological and connective tissue reactions to damage. Disruption of microcirculation provokes tissue hypoxia, activation of free radical oxidation, disorganization of biological membranes with the release of physiologically active proinflammatory substances (prostaglandins, cytokines), aimed at the destruction of bacterial pathogens.
The importance of lipid peroxidation (LPO) processes in the development of generalized periodontitis has been found out [9]. LPO is normal metabolism, the physiological role of which is to regulate the function of cell membranes, receptors, prostaglandin synthesis [10]. The experimental studies have shown that in animals with spontaneous periodontitis, LPO processes are enhanced, accompanied by hypercoagulation. Data on the pathogenetic role of lipid peroxidation indicate the feasibility of antioxidant therapy aimed at eliminating the destructive effects of LPO products on periodontal
tissues. It is proved that the drug selenium has a positive effect on the clinical course of diseases, blood supply to periodontal tissues and the state of antioxidant protection of oral fluid. In the clinic it has been found out that periodontitis in patients' blood accumulates lipid peroxidation products due to the significant increase of malone dialdehyde with decreasing concentrations of superoxide dismutase and catalase. The results of the study of total antioxidant activity showed that the values of this parameter in the gum tissue in intact periodontitis and generalized periodontitis have significant differences. The hypothetical concept of periodontitis development according to which leukocytes, migrating through gum tissues, focusing on chemotoxic factors (microorganisms, products of their vital activity), cause alteration of own tissues due to intensification of lipid peroxidation processes on their way [11].
One of the mechanisms of damaging action of free radicals is the destruction of phospholipids of cell membranes under the action of activated FLA2, resulting in the release of arachidonic acid, which is a substrate for two main groups of enzymes: cyclooxygenase and lipoxygenase. Cascade metabolism of arachidonic acid leads to the formation of a great number of physiologically active compounds, called eicosanoids in leukocytes, fibroblasts, mast cells, epithelial cells and endothelial cells. Cyclooxygenase leads to the formation of cyclic endoperoxides from arachidonic acid, which are substrates for further conversion to prostaglandins, prostacyclin and thromboxanes. It is shown that the development of periodontitis is accompanied by increased synthesis of prostaglandins [12]. The literature also provides data on the relationship between the severity of the inflammatory process in the periodontium and the increase of arachidonic acid and prostaglandins - PGE2 and PGF2a in gums, oral and gingival fluids. The increase of PGE2 content in periodontal tissues goes hand in hand with the increase of the amount of ionized calcium, with increased mobilization from the alveolar bone, which leads to bone resorption by stimulating osteoclast function [13].
In the literature there is evidence of the role of biogenic amines in the development of inflammatory phenomena in periodontal tissues. In the experiment it was shown that the consequences of intoxication with biogenic amines were changes in the periodontium of animals, similar to those which are observed in cases of periodontitis in humans. In the clinic, it has been found out that the level of histamine in the blood of patients with generalized periodontitis decreases during remission and increases during exacerbation [14].
Interesting results were obtained by the researchers who conducted a comparative analysis of the prevalence of periodontal lesions among the indigenous people of Armenia and the refugee population, which was considered as a group of people under constant stress. Significantly higher spread of periodontitis was observed in refugees, on average, 20% higher. At the same time, pyorrheal forms of
East European Scientific Journal #1(65), 2021 55 lesions with pus were observed in the majority of patients [15].
Stress cell damage is nonspecific. One of its important pathogenetic mechanisms is the violation of the permeability of cell membranes due to the activation of LPO. It is proved that the degree of activation of lipid peroxidation in oral fluid in patients with generalized periodontitis, which occurred under conditions of chronic emotional stress, was significantly higher than in patients working under normal conditions. The condition of periodontal tissues in students in the process of their adaptation to new social and living conditions has been studied. It is noted that disease prevention and correction of maladaptation processes in periodontal tissues should be carried out by introducing the system of treatment and prevention measures that take into account the phases of adaptation under the influence of chronic psycho-emotional stressors. The typological features of the organism, which are highly sensitive to neurohumoral factors, play a significant role in the mechanisms of stress damage to periodontal tissues. The experiment studied the biochemical basis of the mechanisms of damage during chronic stress in animals with different types of response to stress, i.e. with different stress resistance. The connection of catabolic processes in periodontal tissues with chronic stress with typological features of the nervous system has been registered. Thus, in animals with the active type, the most significant catabolic processes have been observed (the level of fucose in the periodontal bone tissue was 30% higher compared to the control). In patients with generalized periodontitis of varying severity, working in conditions of chronic emotional stress, scientists revealed activation of general collagenolytic activity, enhancement of free radical oxidation of lipids in periodontal tissues, oral fluid and blood. It has been found out that the degree of metabolic disorders in periodontitis correlates with individual typological features of nervous regulation [16]. These facts indicate a significant role of stress in the development of periodontal pathology.
Considering the possible causes and mechanisms of generalized periodontitis, taking into account modern ideas about inflammation as a dynamic self-regulating system, researchers have shown that the transition of the pathological process to a prolonged chronic course is observed with reduced functional activity of avant-garde antimicrobial protection, neutrophils and macrophages. Neutrophils play a key role in the development of inflammation and destruction of periodontal tissues, as they are the first to respond to chemotactic factors from dental plaque, infiltrate a large number of periodontal tissues and perform their main effector functions - chemotaxis, adhesion, phagocytosis, oxidation. Thus, gingival fluid, which is an inflammatory exudate from periodontal tissues, contains 95-97% of neutrophils, 2-3% of monocytes, 1-2% of lymphocytes. Neutrophils are characterized by high biological activity. The huge microbicidal and cytolytic potential allows them to effectively neutralize and eliminate pathogens. But at
56 East European Scientific Journal #1(65), 2021 the same time, neutrophils can enhance the destructive processes in periodontal tissues [17]. When they interact with bacteria, many biologically active substances enter the tissues: free radicals, nitric oxide (NO), proteolytic enzymes, including tissue-destructive (elastase, myeloperoxidase, cathepsins B, D, G, etc., matrix metalloproteinases - M, MMP-9), products of arachidonic acid metabolism (eicosanoids -leukotrienes, prostaglandins, etc.), various cytokines
[18]. The presence in neutrophils of the transcription factor NF-kB, which controls the expression of genes encoding the synthesis of many cytokines and chemokines, adhesive proteins, enzymes that regulate cell growth and apoptosis has been proved. Therefore, in the light of modern ideas, neutrophils are considered not only to be effector cells. They are able to have a significant regulatory effect on other blood cells, including immunocompetent, endothelial and connective tissue cells, on various enzyme systems
[19].
Cells of monocytic-macrophage series, as well as neutrophils, perform the function of factors of nonspecific resistance (non-immune phagocytosis, secretion of antibacterial products, antibody-independent cytotoxicity), but are actively involved in specific immune responses (transporting of antigens to lymphoid cells, secretion of interleikenes and components of complement). Macrophages are the main producers of cytokines that regulate the course of inflammatory and immune reactions in the periodontium [20].
Lymphocytes are the main cells of the immune system that are involved in the fulfilling of the main function of acquired specific (adaptive) immunity: the recognition and elimination of foreign macromolecules, as well as the production and secretion of antibodies (immunoglobulins). In the implementation of the humoral response, the main role is played by B-lymphocytes, which differentiate into antibody producers under the influence of the antigenic stimulus. In this case, B-lymphocytes need the help of T-helpers and antigen-presenting cells. The cellular immune response involves the accumulation in the body of the clone of T lymphocytes that carry specific for this antigen antigen-recognizing receptors and those receptors which are responsible for cellular immune inflammation responses - delayed-type hypersensitivity, in which, in addition to T lymphocytes, macrophages are involved. The result of the effector phase of the immune response is the elimination of antigen with the participation of activated lymphocytes, their products, as well as other cells and mechanisms of nonspecific protection involved by lymphocytes in the specific immune response - phagocytic cells, NK cells, complement system [21].
In patients with generalized periodontitis, immunological reactions develop both in the local immune system of the oral cavity and in the body in the whole [22]. It is proved, that patients with chronic periodontitis have impaired peripheral tolerance mechanisms, manifested by the decrease in the
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proportion of Treg regulatory cells in the peripheral blood. This can lead to hypersensitivity of the host immune system and the development of chronic inflammation in response to biofilm antigens, which cannot be solved spontaneously after the elimination of the irritant. Different clinical variants of periodontitis are characterized by ambiguous disorders of immune status [23]. The state of systemic immunity depending on the severity of generalized periodontitis is described. Many authors believe that dysfunction of the immune system in patients with generalized periodontitis is either the consequence of genetic predisposition, or develops against the somatic pathology of internal organs, endocrine disorders, chronic viral, bacterial and fungal infections. Recently, there have been studies in which it has been shown that prolonged chronic inflammatory process in periodontal tissues itself can also lead to the development of immunodeficiency [24]. In addition, there are atypical, "aggressive" forms of periodontitis, for which the failure of immune mechanisms is the main cause of the disease. Thus, in patients with juvenile periodontitis, along with the specific microflora of periodontal pockets, genetically determined disorders of the immune system, mainly associated with DR-locus antigens of the HLA system (Human Leukocyte Antigen) class II are revealed. The detected decrease in the chemotactic activity of neutrophils in patients with juvenile periodontitis is associated with the genetically determined decrease in the number of leukocytes on the surface of specific N-formyl-methionyl-leucyl-phenylalanine receptors for chemotactic lipids. The decrease in phagocytic active leukocytes is explained by the polymorphism of Fc-gamma receptors on neutrophils and monocytes / macrophages, which leads to the violation of their binding to the Fc fragment of the immunoglobulin G molecule after opsonization with microorganisms and thus slows down phagocytosis [25]. The predominance of cellular or humoral immunity in response to an infectious or other foreign antigen is determined both by the nature of the antigen and the competitive relationship between the two types of helper T lymphocytes (T-helper inducers, Th). Some of them -Th1 - produce IL-2, TNF and cause the cellular immune response; others -Th2 - produce IL-4, IL-10 and promote the predominance of humoral immune response with the production of specific antibodies. In most cases, the immune system is able to create the type of immune response that is most effective for a given type of pathogen or antigen [26]. It is shown that the indicators of immunological status in patients with chronic periodontitis are characterized by the significant decrease in natural killers (CD16), phagocytic activity of granulocytes and immunoglobulins of classes M and G [27]. Thus, the current level of clinical immunology, advanced methods of immunological research allow to obtain more complete information about the various parameters and components of the immune system and to constantly monitor them during treatment, which is a necessary condition for rational immunocorrection.
Summarizing the above-mentioned information, we can assume that the intercellular and intersystem interaction involving different populations of leukocytes and substances produced by them determines the nature and rate of development, intensity and prevalence of the inflammatory process in periodontal tissues. Complex pathochemical reactions are interconnected by specific mediators of intercellular interactions - cytokines, which for the implementation of their function bind specific receptors that are normal or appear when activating target cells on their membrane. The term "cytokines" combines "growth" factors that regulate the proliferation, differentiation and function of blood cells, including cells of the immune system. Cytokines are products of immunocompetent cells, and at the same time, immunocompetent cells are targets of cytokines. Cytokines are secreted mainly by blood and immune system cells (polymorphonuclear leukocytes, macrophages, lymphocytes) and have autocrine (on the cells that produce them), paracrine (on cells in the microenvironment) and endocrine (on distant cells) effects. In this case, they interact with each other on antagonistic and agonistic principles and form a cytokine network in the body. To perform their function, cytokines bind specific receptors that are normal or appear upon activation of target cells on their membrane [28]. According to the main mechanisms of action, cytokines are divided into: growth factors that control the production of immunocompetent cells (colony-stimulating factors - G-CSF, M-CSF, GM-CSF; transforming growth factor beta - TGFP, etc.); proinflammatory cytokines that provide mobilization and activation of cells involved in inflammation (interleukins - IL-1, IL-6, IL-8, IL-12; tumor necrosis factor alpha - TNFa; interferons - IFN and INFy; factor that inhibits migration - MIF ); anti-inflammatory cytokines with the alternative nature of action that limit the development of inflammation (IL-4, IL-10, IL-13, TGFP); cytokines that regulate the cellular and humoral immune response (IL-1, IL-2, IL-4, IL-5, IL-6, IL-7, etc., IFN, TGFP); cytokines with their own effector functions (antiviral, cytotoxic) [29]. Cytokines control the process of angiogenesis, regeneration processes, metabolic processes, etc. The action of cytokines may be associated with morphofunctional disorganization of the endothelium and serious microcirculation disorders in a variety of pathological conditions, including inflammation. In recent decades, the role of cytokines in the development of immunological and inflammatory reactions in periodontitis has been studied [30]. Maximum local release of proinflammatory cytokines transforms the protective mechanisms into pathological, uncontrollable, which causes damage to periodontal tissues and bone resorption. A certain complex of cytokines, including IL-1, TNFa, IL-6, etc., determines the course of inflammation in the focus of tissue destruction that occurs in cases of generalized periodontitis. The formation of granulation tissue in the focus of chronic inflammation (periodontal pocket) is the result of the action on its cellular elements of growth factors of
East European Scientific Journal #1(65), 2021 57 different genetic orientation, which are produced by macrophages, lymphocytes and fibroblasts. The study of the level of various cytokines in the gingival fluid in patients with periodontitis showed significant changes in the composition and titer of cytokines compared with those with intact periodontium. The content of pro-inflammatory cytokines IL-1P, which is the initiator of the cytokine cascade in periodontal tissues, in patients with periodontitis increases in the gingival fluid 3 times compared with the level of healthy people. The level of anti-inflammatory cytokine IL-4 is significantly reduced, which is an unfavorable sign in the course of chronic periodontitis, as it leads to uncontrolled activation of macrophages and their production of IL-1, TNFa and other cytokines. The expression of IL-6 and IFN is significantly higher in the tissues of patients with inflammatory periodontal disease compared to the tissues of healthy individuals . The content of IL-1 and TNFa in gingival fluid and peripheral blood serum was studied. It was shown that the level of IL-1 in the gingival fluid correlates with the depth of periodontal pockets. In addition, the level of IL-1 in the serum was significantly lower than in the gingival fluid, which indicated the presence of local mechanisms of production of this cytokine and its importance in the pathogenesis of periodontal disease [31].
One of the most significant achievements of recent decades in periodontology can rightly be considered revealing of the mechanism of destruction of the periodontium itself [32]. In the destruction of connective tissue structures of the periodontium the main role is attributed to specific proteases (generalized "collagenases"). There are bacterial proteases produced by periodontal bacteria (for example, collagenases Porphyromonas gingivalis) and proteases that are synthesized and secreted by cells of the host, the so-called matrix metalloproteinases (MMP) [33]. Matrix metalloproteinases belong to the family of zinc metalloproteinases, the function of which is associated with the metabolism of the connective tissue matrix in normal and pathological conditions. There are more than 20 members of this family, which on the basis of domain structure and substrate specificity can be divided into 6 subfamilies: collagenase, gelatinase, stromelysin, membrane type MMP, matrilysin, and MMP, which do not belong to the known subgenera. The activity of MMPs in tissues depends on the level of expression of their genes, on the presence of activators (integrins, cytokines, lipopolysaccharide, proteases, etc.) and specific tissue inhibitors . The participation of a number of MMPs in the destruction of periodontal tissues has been found out. It has been shown that endogenous inhibitors in areas of active tissue destruction are insufficient to regulate the increased activity of MMPs [34].
Longitudinal clinical study during the year on the dynamics of the pathological process in periodontal tissues in young people (18-25 years) with different molecular genetic profile allowed to reveal the dependence of clinical manifestations of generalized periodontitis from the individual variant of the genetic profile [35].
Significant interest of researchers is currently occupied by studying the mechanisms of development of the destructive process in the alveolar bone in patients with generalized periodontitis. It has been revealed that the destruction of bone tissue occurs when the remodeling process is inconsistent: either with increased bone resorption (increased osteoclast activity), or with insufficient bone formation (decreased osteoblast activity), or when both processes are disrupted simultaneously. Revealing of factors that determine the development of alveolar bone destruction in patients with GP is of particular interest. It is shown that one of the mechanisms of development of the destruction process is the synthesis of periodontopathogenic bacteria cytokines that stimulate bone resorption. It is known that the endotoxins of gram-negative bacteria - lipopolysaccharides (LPS) are the strongest stimulators of the production of macrophages and fibroblasts of the periodontal ligament of proinflammatory cytokines (IL-1, IL-6, TNFa) and prostaglandin E2 [36]. Thus, lipopolysaccharide A. actinomycetemcomitans and Porphyromonas gingivalis, which was injected into the gums of mice, has been shown to enhance the production of IL-1a and IL-1P in periodontal tissues and induce bone resorption. The lipopolysaccharide Prevotella nigrescens stimulates osteoclastogenesis in vitro by increasing GHG E2 production. Lipopolysaccharide extract Prevotella intermedia in vitro inhibits the activity of alkaline phosphatase of osteoblasts dose-dependently and inhibits mineralization (calcium content), as well as induces the production of osteolytic factors - nitric oxide, IL-6, MMP-2, -9. It has also been found out that extracts from cultures of Prevotella intermedia and A. actinomycetemcomitans in vitro inhibit the activity of alkaline phosphatase of osteoblasts, thereby inhibiting the process of bone formation and stimulate bone resorption [37].
Significant progress in understanding osteoclastogenesis has been made with the discovery of receptors (RANKL-RANK-OPG), which play a key role in the proliferation, differentiation and activation of osteoclasts [38]. It is shown that in patients who addressed for orthodontic treatment with varying degrees of periodontitis against the metabolic syndrome, there is an increase in gum tissue methylation level of the RANKL gene promoter in chronic generalized periodontitis II-III degree compared with initial-I degree, indicating increased resorption RANKL gene [39]. The molecular basis of intercellular interaction can be represented as follows: RANKL (receptor activation of NF-k-ligand) - a transmembrane ligand expressed on the surface of osteoblasts, fibroblasts and activated T lymphocytes. It binds RANK -receptor expressed on hematopoietic progenitor cells of osteoclasts, and induces the process of differentiation and maturation of osteoclasts. With the loss of RAKL expression there is a defect in the early differentiation of T- and B-lymphocytes, which provides the prerequisites for understanding the interaction of processes occurring in bone tissue and the
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immune system. RANKL is absolutely necessary for the development of osteoclasts. Increased RANKL expression leads to bone resorption and, consequently, to bone loss. OPG-osteoprotegerin is a glycoprotein that is widely expressed in various tissues, has a strong inhibitory activity of osteoclastogenesis, i.e. is a strong inhibitor of bone resorption. OPG acts for RANKL as an imaginary receptor, blocks the interaction with RANK and thus inhibits the formation of mature osteoclasts, disrupts the process of osteoclastogenesis and bone resorption. The balance between RANKL and OPG actually determines the amount of bone resorbed. It should be emphasized that the regulatory proteins RANKL-RANK-OPG are considered the most important mediators among all other systems in the process of bone remodeling, both in normal and in various osteopathies. The crucial importance of the system of regulatory proteins RANKL-RANK-OPG in the regulation of resorptive activity of osteoclasts, namely in their differentiation from progenitor cells and activation of mature osteoclasts. It has also been shown that lipopolysaccharide of gram-negative bacteria and some proinflammatory cytokines (IL-1P, TNF) are directly involved in the differentiation and activation of osteoclasts through activation of NF-kB, thereby enhancing osteoclast-mediated bone resorption. Many works both on the modulation of the RANKL-RANK-OPG signaling pathway and its role in the resorption of the alveolar bone have been published in stomatological editions. It has been shown that the increased RANKL / OPG ratio is associated with the ability to support osteoclast formation and activation. When cells differentiate, the RANKL / OPG ratio decreases. The imbalance of the RANKL-RANK-OPG system leads to serious disorders of bone remodeling. Thus, it has been found out that A. actinomycetemcomitans induces the development of experimental periodontitis in mice, causes leukocyte infiltration in periodontal tissues, expression in MMP tissues (MMP-1, -2, -9), RANKL, OPG, cytokines (TNFa, IL-1P) , which leads to increased bone resorption [40]. From the abovementioned facts we can conclude that the significant role in the resorption of alveolar bone belongs to proinflammatory cytokines, prostaglandin E2 and the regulatory protein system RANKL-RANK-OPG, which determines the pathways of drug correction of alveolar bone remodeling.
The process of bone remodeling depends not only on bone resorption, but also on the rate of bone formation and the ability of osteoblasts to form a full-fledged new bone, and this is directly related to the state of bone metabolism and calcium-phosphorus homeostasis. It is known that three main hormones are involved in the maintenance of calcium-phosphorus homeostasis: parathyroid hormone (PTH), calcitonin and the active metabolite of vitamin D - calcitriol [41]. The action of parathyroid hormone is aimed at maintaining and increasing the concentration of calcium in the body. Hypocalcemia stimulates linear increase in PTH, and decrease in calcium to 1.75 mmol / l causes a sharp increase in its secretion. The effect of PTH is achieved by mobilizing calcium from the bones
into the extracellular fluid. With the further increase in the concentration of this hormone, along with demineralization, the destruction of the organic matrix of bone occurs, as evidenced by the increase in the secretion of hydroxyproline in the urine. The mechanism of action of vitamin D3 is to increase the synthesis of proteins responsible for the transportation of calcium and phosphorus from the intestine. Vitamin D3 acts as an active bone remodulator. The anabolic effect of the active metabolites of vitamin D3 on bone tissue is manifested by the increase of its mineralization by increasing the synthesis of osteocalcin, deposition of calcium and phosphorus in the bones. However, osteocalcin increases the proliferation of osteoclasts, reduces collagen synthesis, which results in increased bone resorption. In the kidneys, osteocalcin increases the reabsorption of calcium and phosphorus by activating transport proteins. Calcitonin secretion increases with the increased load on organs and systems (pregnancy, lactation) and aims at reducing the release of components of the mineral and organic matrix of bone tissue, which leads to the decrease in the concentration of calcium and phosphorus in the serum [42].
Magnesium also plays an important role in bone metabolism. Its role is assessed from the standpoint of its unique ability to act as a natural calcium antagonist, thereby regulating the implementation of a variety of vital functions that depend on the presence of calcium ions. It is believed that the optimal ratio of calcium and magnesium is 2:1. Magnesium deficiency reduces the bioavailability of calcium, leads to hypocalcemia, decreased secretion of parathyroid hormone and calcitriol, contributing to the development of osteoporosis. With the excess of magnesium in the diet the decrease in calcium excretion in the urine has been revealed, which may play a role in the development of disorders of the structural and functional state of bone tissue. In addition, excess magnesium accelerates bone metabolism, mainly by stimulating osteoclasts. Many scientific studies, especially by domestic authors, are devoted to the study of osteogenesis disorders in patients with generalized periodontitis and the relationship of these disorders with the state of the skeletal system in the whole. Analysis of these studies suggests common etiological and pathogenetic factors in the development of generalized periodontitis and systemic osteopathy (osteopenia, osteoporosis) [43]. It has been revealed that patients with GP, regardless of the severity, suffer from disorders of metabolism of the main protein of connective tissue - collagen and mineral metabolism. The most vivid changes are observed on the organic basis, as evidenced by increased collagenase activity and deviations in the content of both free and protein-bound hydroxyproline - markers of the catabolic and synthetic phases of collagen metabolism. Among the indicators of mineral metabolism the decrease in calcium levels and alkaline phosphatase activity in the serum should be taken into consideration. The connection between the structural and functional state of periodontal tissues and the skeletal system in people of different ages and genders
East European Scientific Journal #1(65), 2021 59 has been revealed. It is shown that the decrease in bone mineral density in systemic osteoporosis is accompanied by the progression of dystrophic-resorptive processes in periodontal tissues, destruction of interalveolar bone septa, inconsistency of processes of remodeling of the organic bone matrix [44]. Peculiarities of the clinical course of generalized periodontitis and structural and functional state of periodontitis in systemic disorders of bone metabolism have been studied: in women during pre- and postmenopause, hypoestrogenism, connected with primary amenorrhea and after the operation of ovarioectomy, in patients with rheumatoid arthritis who take glucocorticoids, etc. Studies have shown that the basis of destructive processes in the alveolar bone in patients with periodontitis against the systemic osteoporosis is increased bone resorption, which is not compensated by normal bone formation [45].
There is no doubt that the concomitant somatic pathology affects the development of inflammatory periodontal disease. It has been proved that in patients with gluten-associated diseases there are factors that affect the progression of periodontal disease [46]. Significant spread and intensity of periodontal inflammation and severe course of this pathology in patients with impaired thyroid function have been revealed [47]. The relationship between the increase in intensity and generalization of the pathological process in periodontal tissues in young people and the duration of endocrine pathology has been found out [48]. Nasal pathology, which causes difficulty in nasal breathing, has been identified as another risk factor for inflammatory periodontal disease [49].
Thus, the given analysis of the literature shows that, according to modern ideas, the role of trigger for the development of inflammatory-destructive process in periodontal tissues belongs to the microorganisms of the dental biofilm. In response to the prolonged persistence of the microflora, chronic inflammation develops, which is the complex of microcirculatory, hematological, immunological and connective tissue reactions to damage. Disruption of microcirculation provokes tissue hypoxia, activation of free radical processes, disorganization of biofilms with the release of biologically active substances (histamine, serotonin), prostaglandins, cytokines, etc. The level of response to damage is determined by the reactivity of the organism. However, the question of clarifying the key mechanisms of development and course of inflammatory diseases of periodontal tissues in each case is relevant, which determines the feasibility of further research.
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