Oxidative stress and its contribution to chronic periodontal inflammation

INTRODUCTION

Periodontitis is a chronic inflammatory disease that affects the tissues that support the teeth, including the gums, alveolar bone, and periodontal ligament. It is one of the most prevalent oral diseases, significantly influencing individual oral health and quality of life.¹

The prevalence of periodontitis globally is 61.6%, while the prevalence of moderate to severe periodontitis is 53.2%.² Thus, periodontitis is considered a prevalent and serious global health issue impacting oral health.

Chronic periodontal inflammation induced by chronic periodontitis is associated with increased oxidative stress and reduced antioxidant capacity in the oral cavity.³ Oxidative stress is a phenomenon occurring when the production of oxygen free radicals and other oxidants in the cellular and extracellular environment exceeds the antioxidants produced by the body, leading to cellular functional damage.^4,5 Oxidative stress is considered a key pathophysiological process that contributes to chronic periodontal inflammation. It may exacerbate inflammatory reactions and worsen the health of gums and surrounding tissues, thus increasing disease severity.^4,5 Furthermore, proteolytic enzymes and reactive oxygen species (ROS), generated through interactions between polymorphonuclear neutrophils and microorganisms, contribute to tissue destruction in the gingival connective tissue and alveolar bone.⁶

Periodontal disease has been linked to various chronic diseases, such as diabetes mellitus, cardiovascular disease (CVD), chronic kidney disease, and liver diseases.⁷ Oxidative stress is a key factor mediating the influence of periodontitis on systemic diseases.⁸ However, the mechanisms of how oxidative stress contributes to chronic periodontal inflammation and how this periodontitis-induced oxidative stress contributes to different chronic diseases are still unclear. The aim of this review is to explore current evidence for data on the contribution of oxidative stress to chronic periodontal disease, highlighting the association between periodontitis-induced oxidative stress and different chronic diseases.

METHODS

A comprehensive literature search was conducted in Medline (via PubMed), Scopus, and Web of Science databases up to 05 May 2025. Medical Subject Headings (MeSH) and relevant free-text keywords were used to identify synonyms. Boolean operators (AND, OR) were applied to combine search terms in alignment with guidance from the Cochrane Handbook for Systematic Reviews of Interventions. Key search terms included: “chronic periodontal inflammation” OR “periodontitis” OR “periodontal disease” AND “oxidative stress” OR “reactive oxygen species”. Summaries and duplicates of the found studies were exported and removed by EndNote X8. Any study that discusses the role of oxidative stress in the pathogenesis of chronic periodontal inflammation and is published in peer-reviewed journals was included. All languages are included. Full-text articles, case series, and abstracts with related topics are included. Case reports, comments, and letters were excluded.

DISCUSSION

Oxidative stress in periodontal disease

Multiple studies have explored the contribution of oxidative stress in the pathogenesis of chronic periodontal inflammation. The role of oxidative stress in the pathogenesis of periodontitis is shown in Figure 1. The presence of dental plaque and its migration to periodontal tissues induces inflammation and leads to the accumulation of leukocytes in the site of infection, especially polymorphonuclear neutrophils.⁹ These polymorphonuclear neutrophils defend against the bacterial pathogens contained within dental plaque through various mechanisms, including phagocytosis, degranulation, NETosis, chemotaxis, and the release of ROS.¹⁰ However, these polymorphonuclear neutrophils may be hyperactivated, leading to overproduction of ROS. Despite the antimicrobial and signaling roles of polymorphonuclear neutrophils and ROS, their overproduction has been linked to various inflammatory diseases, such as type 2 diabetes, atherosclerosis, rheumatoid arthritis, cancer, lung diseases, renal diseases, and periodontitis.^11-15

This can be attributed to the increase in oxidative stress caused by ROS. Oxidative stress results in intracellular damage to proteins, lipids, and DNA, connective tissue destruction, and bone resorption.^15-17 Erythroid 2-related factor 2 (Nrf2) is a key antioxidant regulator down-regulated by oxidative stress, and the suppression of Nrf2 can lead to the progression of inflammatory diseases such as periodontitis and rheumatoid arthritis.¹⁸ ROS-mediated damage also affects extracellular connective tissues, leading to clinical attachment loss.¹⁹

Furthermore, the overproduction of ROS and increased respiratory burst activity from hyperactive polymorphonuclear neutrophils result in the expression of proinflammatory cytokines, neutrophil priming, and prolonged neutrophil lifespan in periodontitis.^20,21 These cytokines play a role in tissue and bone destruction through both direct and indirect mechanisms. A disruption in the RANKL/osteoprotegerin axis may also occur, resulting in increased osteoclastogenesis, further increasing bone resorption.²² This axis is also essential in other inflammatory bone diseases such as osteoporosis and rheumatoid arthritis.¹⁷ Proinflammatory cytokines such as IL-1, IL-6, and TNF-α further contribute to uncoupled bone remodeling and osteoclast activation.²³ Additionally, ROS can reduce collagen synthesis, impair fibroblast function, and induce the overexpression of matrix metalloproteinases (MMPs), which degrade bone and connective matrices.^24-26 An imbalance between MMPs and their inhibitors exacerbates tissue degradation.²⁷

Oxidative stress markers in periodontal disease

Oxidative stress biomarkers are closely linked to the development and severity of periodontitis. Elevated levels of markers like malondialdehyde (MDA), hydrogen peroxide, and oxidative DNA damage, along with reduced activity of antioxidants such as superoxide dismutase (SOD) and catalase (CAT), have been consistently observed in periodontitis patients. These biomarkers correlate with disease progression and severity, making them valuable tools for diagnosing periodontitis and monitoring treatment outcomes.²⁸

Oxidative stress leads to the production of biomarkers, such as MDA, 8-hydroxy-2-deoxyguanosine (8-OHdG), and protein carbonyls, which were found elevated in the saliva, gingival crevicular fluid, and plasma of periodontitis patients.^16,28,29 These oxidative markers correlate with disease severity and tissue attachment loss.

Notably, oxidative stress biomarkers tend to decrease following non-surgical periodontal therapy, such as scaling and root planning, and may respond further to adjunctive antioxidant therapies, highlighting their utility in monitoring treatment response. However, their levels may vary depending on the sampling site and methodology used, raising concerns regarding standardization and reliability. The imbalance in antioxidant defense, marked by diminished SOD and glutathione peroxidase activity, is closely associated with increased oxidative burden and tissue destruction.³⁰ Emerging markers such as isoprostanes and advanced oxidation protein products (AOPP) are being explored for improved sensitivity and specificity.³¹ Individual factors such as smoking, diabetes, and genetic variations affecting oxidative pathways can significantly influence the levels of biomarkers in the body. These factors can lead to increased oxidative stress and inflammation, which are reflected in changes to various biomarkers, suggesting a need for personalized interpretation in clinical settings.

Role of oxidative stress in linking periodontal disease and systemic diseases

Besides damaging periodontal tissues, periodontitis contributes to systemic diseases, such as cardiovascular diseases, diabetes mellitus, chronic kidney diseases, and liver diseases, via mechanisms, including systemic inflammation and oxidative stress.⁷

Cardiovascular diseases

There is a link between periodontal inflammation and CVD through oxidative stress. As mentioned, periodontal inflammation induces the production of ROS, which enter the bloodstream, inducing vascular endothelial dysfunction and enhancing atherosclerotic processes.⁴ ROS also activate redox-sensitive transcription factors like NF-κB, which upregulate proinflammatory cytokines.⁴ It has been reported that patients with both periodontitis and acute myocardial infarction exhibit high levels of lipid peroxides and increased oxidative stress markers.³² Coenzyme Q10, an antioxidant crucial for mitochondrial function, has also been reported to be lower in these patients.³³

Additionally, animal studies reported that periodontitis can stimulate inflammatory and oxidative responses in cardiac tissue, which can be mitigated by antioxidants such as crocin and caffeic acid phenethyl ester.^34,35 In diabetic patients, where mitochondrial ROS production is already elevated, periodontitis may further increase cardiovascular risk.³⁶

Diabetes mellitus

Diabetes mellitus and periodontitis have a bidirectional relationship, mainly driven by chronic inflammation and oxidative stress.³⁷ Oxidative injury and reduced antioxidant capacity are common in both diseases. Studies addressing the diabetes-periodontitis relationship demonstrated increased levels of oxidative biomarkers such as 8-hydroxydeoxyguanosine, MDA, and 3-nitrotyrosine. They also reported a downregulation of Nrf2 expression, a key antioxidant regulator.³⁸ This dual disease state worsens oxidative damage both locally and systemically, leading to more severe periodontal destruction. Notably, rutin and curcumin have been shown to improve antioxidant status and reduce oxidative stress in diabetic periodontitis.³⁹

Chronic kidney disease

Studies have shown that oxidative stress caused by periodontal inflammation may affect renal tissues negatively, resulting in disruption of renal tubules and histomorphological alterations.⁴⁰ Resveratrol, an antioxidant, can restore gingival redox balance and decrease systemic oxidative stress, potentially protecting against kidney damage.⁴¹

Liver injury

Oxidative stress also contributes to liver injury by inducing lipid peroxidation, DNA damage, and mitochondrial dysfunction.⁴² Studies indicate that periodontitis can reduce hepatic glutathione levels and increase oxidative markers such as HEL and 8-OHdG, particularly when combined with other stressors like alcohol.⁴³ This suggests that periodontitis-related oxidative stress may exacerbate hepatic damage.

Oxidative stress precipitating factors

Smoking

Smoking can significantly increase oxidative stress in periodontal disease by accelerating the production of ROS and suppressing antioxidant defense mechanisms. Smoking also induces a hyperactive neutrophil response, resulting in excessive ROS production and cytokine release, which contributes to tissue destruction via oxidative stress.⁴⁴ Multiple studies reported that smoking reduces antioxidant levels, including glutathione peroxidase, superoxide dismutase, and catalase. Smoking also increases markers of oxidative damage, such as 8-hydroxy-2′-deoxyguanosine and C-reactive protein.^45,46 It also disrupts bone homeostasis by promoting osteoclastogenesis and bone resorption and altering the RANKL/osteoprotegerin ratio.⁴⁷ Furthermore, smoking has been associated with reduced treatment response and a dose-dependent decline in antioxidant capacity.⁴⁸ These changes collectively worsen periodontal outcomes and suggest that antioxidant therapies could play a critical role in counteracting smoking-induced oxidative stress in periodontal disease.

Obesity

Obesity contributes significantly to oxidative stress in periodontal disease through chronic systemic inflammation and excessive production of ROS. Adipose tissue in obesity secretes proinflammatory cytokines like TNF-α and IL-6, which disrupt immune regulation and promote oxidative imbalance.⁴⁹ Elevated oxidative markers such as myeloperoxidase, protein carbonyls, and 8-hydroxy-2′-deoxyguanosine have been detected both in serum and gingival crevicular fluid of obese individuals, indicating systemic and local oxidative stress.50 Simultaneously, total antioxidant capacity is diminished, impairing the body’s ability to counteract ROS. This oxidative environment amplifies gingival inflammation and periodontal tissue destruction, even in the absence of active infection.⁵⁰

The bidirectional link between obesity and periodontitis suggests that oxidative stress not only worsens periodontal damage but may also perpetuate systemic inflammation, reinforcing obesity-related metabolic disturbances.⁴⁹

Future directions

Future research should focus more on the mechanisms of antioxidant therapy in reducing oxidative stress in periodontal disease. It should explore how antioxidant therapy improves endogenous antioxidant defenses, reduces ROS production, and regulates inflammatory and immune responses to induce periodontal tissue healing. Understanding these molecular interactions will clarify antioxidant efficacy. Antioxidant therapy can also play a role in personalized therapy. The integration of biomarker and genomics data can result in individualized treatment based on a patient’s genetic background, environment, and health status. Tools like artificial intelligence and big data can support personalized analysis and treatment optimization.

Furthermore, it is critical to improve clinical trial design by prioritizing multicenter, randomized, and double-blind designs with comprehensive assessment metrics, including inflammatory markers and tissue regeneration outcomes. Meta-analyses should also be performed to help synthesize findings and support evidence-based clinical application. More studies should focus on lifestyle factors, such as diet and smoking, as they remarkably impact oxidative stress and periodontitis progression.

Diets low in antioxidants and high in sugars increase oxidative stress, while foods rich in antioxidants (e.g., vitamins C, E, and carotenoids) can help decrease inflammation. Additionally, smoking induces the generation of free radicals and impairs antioxidant defenses, worsening periodontal damage. Addressing such factors is crucial in comprehensive treatment strategies.

Biotechnological innovations like nanomedicine and CRISPR show promise for targeted therapy and tissue regeneration. Nanoparticles can deliver antioxidants directly to inflamed sites, while CRISPR may enable gene editing to reduce inflammation and restore tissue function. Though still in development, these technologies could revolutionize periodontal treatment. Finally, biomarker advancements in genomics and molecular biology can enable more precise treatment approaches. Identifying susceptibility genes and microbial profiles could guide personalized interventions and improve treatment efficacy, supported by multicenter trials and precision medicine frameworks.

Antioxidants in periodontal disease

Antioxidants are compounds produced to neutralize and clear oxygen-free radicals and other oxidants within cells. They play a key role in the prevention and treatment of chronic inflammatory diseases. One of the key antioxidants is vitamin C (ascorbic acid). It is a water-soluble antioxidant that neutralizes hydroxyl radicals (•OH) and singlet oxygen (¹O₂), thus suppressing cellular damage caused by oxidative stress.^51,52 Vitamin C is critical in diseases such as neurodegenerative conditions, CVDs, and cancer.⁵³ Vitamin E (α-tocopherol) is a lipid-soluble antioxidant that is present predominantly in cell membrane phospholipid bilayers. It is capable of suppressing lipid peroxidation by neutralizing lipid peroxides and stabilizing membrane structure.⁵⁴

Glutathione (GSH) is another antioxidant with a tripeptide form (glycine, cysteine, and glutamic acid) crucial for intracellular redox homeostasis. It neutralizes ROS and regenerates its reduced form (GSH) from its oxidized form (GSSG) via NADPH-dependent glutathione reductase, supporting the activity of vitamins C and E.⁵⁵ Reduction of GSH is associated with increased oxidative stress, leading to increased risk of diseases such as periodontitis.⁵⁶

Carotenoids, such as β-carotene, lycopene, and lutein, are fat-soluble antioxidants that neutralize singlet oxygen and other ROS through their conjugated double bond structure.⁵⁷ They protect cell membranes and organelles under oxidative stress. However, under certain environmental conditions, such as high oxygen tension, carotenoids may shift to pro-oxidant behavior.

Oxidative stress can be assessed by antioxidant enzymes, including glutathione peroxidase, superoxide dismutase, and catalase. Antioxidant enzymes are released in response to oxidative stress to restore redox balance.⁵⁸ Non enzymatic antioxidants such as albumin and uric acid are also released to support oxidative stability in the oral cavity.⁵⁹ Multiple studies showed that antioxidant levels increase following periodontal treatment, supporting the association between oxidative stress and periodontitis progression.^6,58,60

A previous study found compromised DNA integrity and reduced antioxidant status in periodontitis patients.⁶⁰ Another study found that levels of uric acid, albumin, total antioxidant capacity, and glutathione peroxidase were restored after nonsurgical treatment.⁵⁸

However, findings on systemic antioxidant status (e.g., in plasma) remain debatable. Notably, total antioxidant capacity showed no differences between healthy and diseased individuals in some studies, while others reported that total antioxidant capacity decreases because of inflammation rather than being a cause.^61,62

CONCLUSION

Oxidative stress plays a central role in the pathogenesis and progression of periodontitis, contributing to local tissue destruction and systemic inflammatory effects. The overproduction of reactive oxygen species, particularly by hyperactive polymorphonuclear neutrophils, leads to cellular and extracellular damage, promoting periodontal tissue breakdown and alveolar bone resorption. Moreover, oxidative stress serves as a key mechanistic link between periodontitis and systemic diseases such as CVD, diabetes, chronic kidney disease, and liver injury. Future research should focus on clarifying molecular pathways, improving antioxidant-based therapies, and integrating personalized approaches through genomics and biomarkers. Targeting oxidative stress represents a vital strategy for preventing periodontal progression and its systemic consequences.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

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