## 4 Discussion
[25] reported that alveolar bone loss around teeth was significantly less among younger non-smokers (\(\leq\)45 years of age) than old non-diabetic smokers (\(\geq\)65 years of age). Furthermore, subjects in group-1 (smokers with peri-implantitis) had a cigarette smoking history of one cigarette per day over the past two years. It is possible that participants with such a brief history of tobacco smoking may exhibit better radiographic bone levels when compared with subjects with a prolonged history of cigarette smoking, (i.e., \(>\)15 packs per year) [14]. However, further research is required for testing these hypotheses. The current study reports that TNF-\(\alpha\), MMP-1, and IL-8 levels were significantly raised among smokers and never smokers with peri-implantitis than never smokers without peri-implantitis. TNF-\(\alpha\), MMP-1, and IL-8 appear to have a crucial role in the destruction of the peri-implant tissue. TNF-\(\alpha\) is a proinflammatory mediator and its level reflects the bacterial amount and the levels of inflammation [40]. MMPs are considered to be involved in wound repair, normal tissue turnover, and periodontal destruction; MMP-1 may initiate the deterioration of the extracellular matrix. Overproduction of MMP-1 may cause accelerated degradation of the matrix in pathologic conditions including peri-implantitis [41]. IL-8 increase causes the activation of polymorphonuclear cells and influences their selective migration from gingival blood vessels. This leads to an increased amount of cells in a limited time and produces inflammatory conditions. Hence, an excessive quantity of IL-8 might indicate the incipient stage of peri-implantitis [42]. Several studies have reported that the secretion of TNF-\(\alpha\), MMP-1, and IL-8 is upregulated by nicotine in tobacco; which appears to play a vital role in the destruction of alveolar bone around dental implants and natural dentition [17]. Elevated levels of these proinflammatoryaty cytokines have been observed in the PICF of patients with peri-implantitis [43]. Moreover, a meta-analysis reported that cigarette smoking jeopardizes bone-to-implant contact by impairing new bone formation around the dental implant [44]. Another explanation in this regard is that cigarette smoking escalates the production and accumulation of AGEs in periodontal tissues [39]. Strong interfaces between AGEs and RAGEs have been linked with the production of ROS that promotes oxidative burst within gingival tissues, functional changes of phagocytosis and chemotaxis of polymorphonuclear cells (PMNs), alleviated formation of antibodies, increased attachment of bacterial adhesion, and raised local and systemic burden by escalating the expression of cytokines in the crevicular fluid and serum [45]. These mechanisms have been associated with the inflammation of oral connective tissues and destruction of alveolar bone around dental implants and natural teeth in cigarette smokers [16]. In literature, a dearth of reports exist that assessed SPP and its association with the inflammatory cytokines' levels discharged saliva, serum, or PICF. In this aspect, the authors hypothesized that PICF levels of TNF-\(\alpha\), MMP-1, IL-8 are raised in smokers with peri-implantitis with high SPP scores than non-smokers with and without peri-implantitis. The findings of the present study are in opposition with this hypothesis as no statistically significant association between SPP and PICF levels of TNF-\(\alpha\), MMP-1, IL-8. One justification in this regard might be that an array of factors such as coping strategies, cognition, expectations, beliefs, and interpretation influence pain evaluation. Furthermore, from these findings, it is not possible to calculate the minimum amount of proinflammatory cytokines required to evoke SPP in individuals with peri-implantitis. Despite a well-documented association between pain conditions and cytokines [46; 47], the association between pain perception and cytokine expression in oral fluids remains unclear and poorly understood.