Periodontitis is a prevalent inflammatory disease, influencing at least 10% of people worldwide (Richards, 2014). It can result in the destruction of teeth supporting tissue and ends up with a loss of teeth. In addition, periodontitis has been suggested to have moderate association with several systemic diseases, e.g., cardiovascular disease, diabetes, and adverse pregnancy outcomes (Nazir, 2017). Current concept suggests that this inflammatory disease is initiated by bacterial infection and subsequently progressed by aberrant host response, which mainly contributes to periodontal tissue destruction (Bartold and Van Dyke, 2013).

In recent years, reactive oxygen species (ROS) have gained more and more attention, because of their central role to the progression of many inflammatory diseases (Mittal et al., 2014). ROS are described as oxygen free radicals and other non-radical oxygen derivatives involved in oxygen radical production (Lushchak, 2014). They are involved in normal cellular metabolism and continuously generated by the cells in most tissues. Another category of substances called antioxidants exist in the cells and can effectively delay or inhibit ROS-induced oxidation (Sies, 1997). Under physiological conditions, ROS are effectively neutralized by antioxidants, which prevent ROS-mediated tissue damage. When inflammation happens, ROS production is drastically increased mainly due to cells of innate immune system, e.g., neutrophils and macrophages during the process of phagocytosis via the metabolic pathway of the “respiratory burst” (Mittal et al., 2014). Subsequently, high levels or activities of ROS cannot be balanced by the antioxidant defense system, which leads to the oxidative stress and tissue damage (Sies, 1997). ROS can directly cause tissue damage, involving lipid peroxidation, DNA damage, protein damage, and oxidation of important enzymes; meanwhile, they can function as signaling molecules or mediators of inflammation (Chapple and Matthews, 2007).

Over the past few years, numerous clinical and basic experimental studies have shown a strong association between oxidative stress and periodontitis. Getting a better understanding of this association can give us a deeper insight into the pathogenesis of periodontitis, relationship between periodontitis and systemic inflammation, and therapeutic strategies. Therefore, the aim of this review is to summarize the current findings of the association between local and systemic oxidative stress and periodontitis.

Neutrophils are the most abundant blood white cells and belong to first defense line against bacterial infection. After initiation of the host response by pathogenic biofilm, neutrophils become the most common inflammatory cells gathering in periodontal tissue and gingival sulcus and they are believed to be the predominant source of ROS in periodontitis (Miyasaki, 1991). Following the stimulation by pathogens, neutrophils produce O2- via the metabolic pathway called “respiratory burst” catalyzed by NADPH oxidase during phagocytosis (Chapple and Matthews, 2007). O2- can be released into phagosomal and extracellular environment and then converted to different radical and non-radical derivatives, such as hydrogen peroxide (H₂O₂), hypochlorous acid (HOCl), hydroxyl radical (OH•) and singlet oxygen (¹O₂). Figure 1 shows the mechanisms of increased ROS production in periodontal disease.

Numerous studies focused on the peripheral blood neutrophils of periodontitis patients and showed that their activity of producing ROS is higher compared to neutrophils from healthy individuals (Gustafsson and Asman, 1996; Fredriksson et al., 1998, 2003; Gustafsson et al., 2006; Matthews et al., 2007a,b; Wright et al., 2008; Aboodi et al., 2011; White et al., 2014; Ling et al., 2016). Consistent results have shown that peripheral blood neutrophils of people with chronic periodontitis (CP) or aggressive periodontitis (AgP) generate significantly more ROS upon simulation with purified immunoglobulin opsonized Staphylococcus aureus compared with peripheral blood neutrophils of healthy controls suggesting that people with periodontitis have a hyper-reactive phenotype of neutrophils and these neutrophils can be stimulated by the Fc-gamma receptor (FcγR) pathway (Gustafsson and Asman, 1996; Fredriksson et al., 1998; Gustafsson et al., 2006; Matthews et al., 2007a). One study by Fredriksson et al confirmed that increased ROS production by neutrophils of periodontitis patients occurs via the stimulation of FcγR pathway and not via complement receptor CR3 or intracellular protein kinase C enzyme (Fredriksson et al., 2003). Hyper-reactivity of both periodontitis patients and control neutrophils was also shown upon the stimulation of unopsonized periodontal pathogen Fusobacterium nucleatum (Matthews et al., 2007a). It has been shown that even without any stimulation neutrophils of periodontitis patients release more extracellular ROS than neutrophils of healthy controls (Matthews et al., 2007a; Ling et al., 2016). One longitudinal study showed that periodontal therapy could reduce FcγR-stimulated (with/without priming with Porphyromonas gingivalis and F. nucleatum) ROS production, but had no effect on unstimulated extracellular ROS (Matthews et al., 2007b). The same study observed that unstimulated ROS production was higher in periodontitis patients than in healthy controls therefore it was concluded that both constitutive and reactive mechanisms contribute to the hyperreactivity of neutrophils in periodontitis (Matthews et al., 2007b). A recent study demonstrated that peripheral blood neutrophils of CP patients produced more extracellular superoxide with or without stimulation of unopsonized F. nucleatum, P. gingivalis and phorbol myristate acetate and this superoxide overproduction was reduced upon non-surgical therapy, indicating that the hyperactivity of neutrophil is related to both reactive and constitutional mechanisms (Ling et al., 2016). Additionally, the level of superoxide released by unstimulated pre-therapy neutrophils significantly positively correlated with the level of C-reactive protein in plasma (Ling et al., 2016). This correlation might be partially explained by the fact that CRP increases toll-like receptor(s) induced superoxide released by neutrophils thus increasing oxidative stress (Ling et al., 2014). There are also studies suggesting an association between NADPH oxidase and FcγR polymorphism and periodontitis (Nibali et al., 2006; Dimou et al., 2010). These studies support the idea that an increased ROS generation in periodontitis could be not only due to stimulation by pathogens but also is genetically predisposed (Giannopoulou et al., 2008).

In vitro studies show that not only neutrophils but also other phagocytes and cells of periodontal tissues, e.g., monocytes, gingival fibroblasts and periodontal ligament cells exhibit enhanced ROS production upon stimulation by periodontal pathogens and/or their components (Bullon et al., 2011; Chang et al., 2013; Golz et al., 2014). However, their contribution into oxidative stress in periodontitis still remains to be elucidated by future studies.

ROS are very active and their life time is extremely short. They can cause direct damage to the tissues resulting in a variety of metabolites of lipid peroxidation, DNA damage, and protein damage, which are usually used to evaluate the destruction of tissue by ROS (Chapple and Matthews, 2007).

Under normal physiological conditions, there is a balance between ROS and antioxidants. Oxidative stress happens only when the antioxidant defense system could not neutralize the elevated ROS production (Sies, 1997). Antioxidants can be classified as two categories based on their mode of function (Chapple and Matthews, 2007). First category comprises preventive antioxidants including enzymatic antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase, and DNA repair enzymes, as well as some metal ion sequestrators such as albumin. Second category comprises scavenging antioxidants or chain breaking antioxidants such as ascorbic acid (vitamin C), carotenoids (including retinol-vitamin A), uric acid, α-tocopherol (vitamin E), reduced glutathione, and polyphenols (flavenoids). Table 4 summarizes the studies investigating the relationship between antioxidants and periodontitis.

SOD and CAT activities were measured in human gingival tissue and these activities were found to be reduced with the increasing periodontal pocket depth (Ellis et al., 1998). The activities of SOD and GPx in saliva were decreased in periodontitis patients (Canakci et al., 2009). Additionally, this study suggested a significant negative relationship between the level of 8-OHdG and MDA and the activities of SOD and GPx, whereas no correlation between clinical parameters and the enzymatic antioxidants activities was observed. Another study showed that the activities of antioxidant enzymes SOD, CAT, and glutathione reductase in saliva of periodontitis patients exhibited a significant negative correlation with periodontal parameters (Trivedi et al., 2015). In contrast to these studies, Panjamurthy et al. showed that activities of enzymatic antioxidants including SOD, CAT measured in plasma, erythrocytes and gingival tissues were elevated in periodontitis, whereas activities of non-enzymatic antioxidants including vitamins E, vitamin C, and reduced glutathione were decreased in periodontitis (Panjamurthy et al., 2005). Similarly, another study by Novakovic et al. showed higher activities of enzymatic antioxidants including SOD and GPx and lower activities of non-enzymatic antioxidants in saliva of periodontitis patients (Novakovic et al., 2014). Furthermore, periodontal treatment resulted in elevating the activities of albumins, uric acid, and GPx and decreasing the activity of SOD (Novakovic et al., 2014). The activity of uric acid was found to be lower in saliva of periodontitis patients and it was shown to be negatively correlated with bone resorption biomarkers such as C-terminal telopeptide of type I collagen and matrix metalloproteinases-8 (Miricescu et al., 2014). Therefore, current results on the relationship between periodontal status and enzymatic antioxidants activity are contradictory. Meta-analysis performed with 6 articles investigating the levels of circulating SOD found no significant difference in this parameter between periodontitis patients and healthy controls (Liu et al., 2014). In contrast, the results for non-enzymatic antioxidants are rather consistent and they suggest that the decreased activities of non-enzymatic antioxidants are associated with periodontitis. Thus, more additional well-designed studies are still required to clarify the relationship between enzymatic antioxidant activities and periodontitis.

Similarly to ROS production, numerous studies indicate that the changes in the activity of antioxidants in periodontitis are influenced by systemic conditions (Garg et al., 2006; Maxwell et al., 2006; Akalin et al., 2008, 2009; Agnihotri et al., 2009; Tonguc et al., 2011; Duarte et al., 2012; Trivedi et al., 2014). One study showed that women have lower activity of vitamin A and urate in serum than men (Maxwell et al., 2006). Gingival activities of specific antioxidants like SOD, CAT, and GPx could be increased by smoking among people with periodontitis, and these changes were considered as a protective or adoptive mechanism (Tonguc et al., 2011). In contrast, another study indicated a compromised activity of gingival SOD and glutathione in smokers (Garg et al., 2006). Smoking is also associated with decreased levels of SOD in GCF and saliva in both periodontitis patients and healthy individuals (Agnihotri et al., 2009). Diabetes mellitus can increase the activity of SOD and gene expression of SOD1 in gingival tissue of periodontitis patients (Akalin et al., 2008; Duarte et al., 2012). However, higher activities of SOD, CAT and glutathione reductase were found in saliva and plasma of systemically and periodontally healthy individuals compared to those with CP and/or diabetes mellitus (Trivedi et al., 2014). Activities of SOD were also found to be decreased by pregnancy among periodontitis patients (Akalin et al., 2009).

Antioxidants present a strong defense function against ROS; therefore, numerous studies tried to examine the application of antioxidants in the treatment of periodontitis. It has been shown that supplemental periodontal treatments with antioxidants like vitamin E, taurine and lycopene result in improved clinical periodontal parameters, higher activities of local and systemic antioxidants, and lower levels of local and systemic ROS compared with conventional periodontal treatment (Arora et al., 2013; Singh et al., 2014; Sree and Sethupathy, 2014). A recent review concluded a useful effect of vitamin C on maintaining periodontal health for elderly people (Alagl and Bhat, 2015). Another recent review focused on the effects of the complimentary use of lycopene, vitamin C, vitamin E, capsules with fruits/vegetables/berry and dietary interventions to periodontal therapy (Muniz et al., 2015). It confirmed that only the use of lycopene and vitamin E is associated with improved clinical parameters (Muniz et al., 2015). These results indicate a promising use of antioxidants for periodontitis treatment, which could be beneficial for both periodontal status and systemic oxidative status.

It has been confirmed that periodontitis is associated with a hyperactivity of peripheral blood neutrophils, which are supposed to be the predominant source of ROS. Recent reports suggest that hyperactivity of neutrophils is likely to be a host-immune reaction to the inflammation of periodontitis, which might be also genetically predisposed. Numerous studies suggested that periodontitis could contribute to both local and systemic oxidative stress. Products of lipid peroxidation, protein damage and DNA damage can be used as the biomarkers of oxidative stress associated with periodontitis. Local and systemic activities of antioxidants can also be influenced by periodontitis. Some studies suggested decreased activities of enzymatic antioxidants, like SOD and CAT, are associated with periodontitis, whereas others showed increased activities of enzymatic antioxidants among people with periodontitis as a protective reaction. The results for non-enzymatic antioxidants as well as TAOC are consistent and indicate compromised antioxidant capacity in periodontitis patients. Different antioxidants have been applied as supplements to the conventional periodontal treatment and optimistic results were obtained, which provides new possibilities in the periodontal therapy. In recent years, TOS and OSI have been used more and more to evaluate total oxidative status or oxidative stress associated with periodontitis. Studies measuring these parameters also confirmed increased local and systemic oxidative stress was associated with the inflammation resulted from periodontitis, but their sensitivity to be used as biomarkers for oxidative stress associated with periodontitis needs to be further verified.

Our review focused on the presence of oxidative stress associated with periodontitis, especially on the relationship between the local and systemic biomarkers of oxidative stress and periodontitis, giving us an implication of pathogenesis of periodontitis through oxidative stress, close relationship between periodontitis and systemic conditions, and promising therapeutic strategies involving antioxidants.

Conception and design: XR-F, OA, and YW. Search references: YW. Drafted manuscript: YW. Critically revised the manuscript: YW, OA, and XR-F.