This dissertation presents a theoretical generalization and provides the solution of the scientific problem that consists in corroborating new approaches to the pathogenetic therapy of inflammatory periodontal diseases based on clarifying the role of redox transcription factors (NF-κB, AP-1, STAT-3, Nrf2) in the mechanisms of dysregulatory functional, metabolic and structural disorders in periodontal tissues of rats exposed to the influence of topical and systemic pathogenic factors.
According to the results obtained, activation of the transcription factors NF-κB, AP-1 and STAT-3 can be considered as a determinant of the pathological system, which results in dysregulation of oxidative metabolism and disorganization of periodontal connective tissue.
It has been found out for the first time that the application of inhibitors of activation of above mentioned factors (ammonium pyrrolidinedithiocarbamate, water-soluble form of quercetin, SR 11302, imatinib mesylate) under systemic inflammatory response restrains the production of reactive oxygen and nitrogen species in the periodontal tissues of the rats: the inhibitors reduce the rate of superoxide anion-radical production by mitochondrial and microsomal electron transport chains, by leukocyte NADPH oxidase, reduce NO-synthase activity (total and its inducible isoforms), lower the concentration of peroxynitrite-ions. As a result, the production of secondary products of lipid peroxidation decreases, while the antioxidant potential of periodontal tissues (when using ammonium pyrrolidinedithiocarbamate, water-soluble form of quercetin and SR 11302) increases as well as the activity of antioxidant enzymes (superoxide dismutase, catalaze). Applying of the inhibitors also limits depolymerization of collagen, proteoglycans and sialoglycoproteins in the soft and bone periodontal tissues, decreases the intensity of the alveolar process resorption.
This research is the first that demonstrates the use of water-soluble form of quercetin during the modelled LPS-induced systemic inflammatory response results in considerable changes in the morphological picture of inflammatory-destructive processes in the periodontal tissues: it prevents the development of purulent exudate, reduces the intensity of the resorption of tooth cementum and bone tissue of the alveolar processes, promotes the formation and maturation of granulation tissue in the walls of periodontal pockets, enhances the replacement of bone defects by connective tissue, and stimulates the regeneration of tooth cementum.
It has been found out the pathogenetic correction of periodontal dysregulatory pathology, which is associated with the development of pathological system resulted from overexpression of NF-κB, AP-1, and STAT-3 transcription factors, can be achieved via the induction of the functionally antagonistic redox-sensitive system Keap1 / Nrf2 / ARE. It has been proven for the first time that the introduction of its epigallocatechin-3-gallate inducer in the simulation of the systemic inflammatory response restrains the generation of superoxide anion radical in the soft periodontal tissues by the mitochondrial electron transport chains, by microsomes and NO-synthase, and by leukocyte NADPH oxidase, and also reduces NO-synthase activity and peroxynitrite concentration. The inhibition of the production of reactive oxygen and nitrogen species results in restraining the activation of lipid peroxidation, enhancing the antioxidant potential of periodontal tissues, and increasing the activity of antioxidant enzymes (superoxide dismutase, catalase).
This research is the first to reveal that the use of epigallocatechin-3-gallate Keap1 / Nrf2 / ARE inducer during the simulation of lipopolysaccharide-induced systemic inflammatory response has been found as effective means to restrain collagenolysis, depolymerization of proteoglycans and sialologlycoproteins in soft and bone periodontal tissues, improves morphological picture of inflammatory destructive processes (prevents the formation of purulent exudate, reduces the intensity of the resorption of tooth cementum and bone tissue of the alveolar process, enhances the formation and maturation of granulation tissues in the walls of the periodontal pocket, promotes the replacement of bone defects by connective tissue, contributes to the cementum regeneration), influences the general signs of systemic inflammatory response (reduces the serum concentration of interleukin-6, tumor necrosis factor, increases the content of interleukin-10, limits the generation of secondary products of lipid peroxidation), restrains hyperinsulinemia, insulin resistance, dyslipidemia.
