EVALUATION OF SALIVARY HMGB1, sTREM-1 AND TNF-α LEVELS IN SMOKING AND NON-SMOKER INDIVIDUALS WITH DIFFERENT PERIODONTAL DISEASES

This clinical study aims to comparatively investigate the salivary levels of HMGB1, sTREM-1, and TNF-α in individuals with periodontitis who smoke and do not smoke, as well as in non-smoking individuals with gingivitis and periodontal health. Based on the results, the study seeks to determine the diagnostic potential of these cytokines in periodontal disease and the effect of smoking on their levels.

Periodontal disease is a multifactorial condition characterized by inflammation of the periodontal tissues, associated with plaque biofilms and mediated by the host response, leading to progressive loss of supporting structures and periodontal attachment. Gingivitis is defined as plaque-induced inflammation of the gingival tissues without loss of attachment. It is a reversible condition that typically resolves within approximately one week following the implementation of oral hygiene measures. It is widely accepted that untreated gingival lesions may progress to periodontitis in susceptible individuals. The transition from gingivitis to periodontitis occurs with the destruction of periodontal ligament fibers and alveolar bone. The most significant predisposing factor for periodontitis is poor oral hygiene, as the primary trigger of periodontitis lesions is microbial dental plaque, which contains numerous pathogenic bacteria. Among these, the red complex-Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola-poses the highest risk for the development of active periodontitis lesions.

Although the pathogenesis of periodontitis is not fully understood, it is well established that tissue destruction is largely due to the host immune response against bacteria and their by-products in dental plaque. The host-pathogen interaction triggers a cascade of immunoinflammatory events, leading to excessive release of proinflammatory cytokines such as interleukin-1 (IL-1), IL-6, prostaglandin E2 (PGE2), and tumor necrosis factor-α (TNF-α), as well as endopeptidases such as matrix metalloproteinases (MMPs), resulting in periodontal breakdown. Inflammation in both localized inflammatory lesions like periodontitis and systemic connective tissue diseases involving multiple tissues and organs is associated with increased levels of cytokines, prostaglandins, and MMPs in affected tissues and systemic circulation.

The available data indicate that periodontal disease exhibits a dynamic pattern of exacerbation and remission characterized by progression and regression of the disease. Different regions in the oral cavity display variable rates of attachment loss, and these regions appear to arise randomly. Active periodontal disease sites are believed to be associated with alterations in the inflammatory cell population, characterized by a significantly higher presence of mast cells, monocytes/macrophages, and plasma cells compared to inactive sites. These cells contribute to the activation and expression of proinflammatory mediators such as IL-1, IL-6, and TNF-α via stimulation of monocytes/macrophages, lymphocytes, fibroblasts, and other related cellular elements. These cytokines and inflammatory mediators promote alveolar bone resorption and collagen degradation, primarily through matrix metalloproteinases, which play a crucial role in tissue destruction associated with periodontal activity.

High mobility group box (HMGB) proteins are non-histone nuclear proteins with various intracellular functions. Initially isolated from the nucleus in the 1970s, they were named for their rapid migration in sodium dodecyl sulfate polyacrylamide gel electrophoresis. The HMGB family includes HMGB1, HMGB2, and HMGB3. While HMGB2 and HMGB3 exhibit limited expression, HMGB1 is widely expressed and its expression is regulated by environmental factors. HMGB1 plays a role in both acute and chronic inflammatory responses, as well as in wound healing. Secreted by activated macrophages, HMGB1 can activate other immune cells, acting as a cytokine. HMGB1 also promotes macrophage activation through HMGB1/RAGE interaction, JNK (c-Jun N-terminal kinase) activation, and upregulation of caspase-3 and caspase-9. Extracellular HMGB1 transmits inflammatory signals by binding to receptors such as RAGE (receptor for advanced glycation end products), TLR-2, TLR-4, and TLR-9. These receptors are believed to play a role in inflammatory processes. HMGB1 is involved in various acute and chronic inflammatory conditions, including rheumatoid arthritis, osteoarthritis, cancer, lupus, and periodontitis. However, only a limited number of studies have investigated the role of HMGB1 in the pathogenesis of periodontitis. Compared to inflamed gingival tissue, higher concentrations of HMGB1 have been detected in gingival crevicular fluid (GCF). Additionally, HMGB1 mRNA and protein levels are highly induced in mouse periodontal ligament fibroblasts stimulated with lipopolysaccharide (LPS) and interleukin-1β. In experimental models, elevated HMGB1 levels, in combination with IL-1β and TNF-α, contribute to alveolar bone loss in periodontitis, suggesting a role for HMGB1 in the disease. However, the mechanism by which HMGB1 contributes to periodontitis and peri-implant diseases, as well as the effect of smoking on salivary HMGB1 levels, remains unclear.