Inflammation: A major link between oral and systemic diseases

Inflammation is a major link between oral and systemic diseases,^1-3 and chronic inflammation often advances silently. In cardiovascular disease, there are strong relationships between the inflammatory marker hsCRP (high sensitivity C-reactive protein) and cardiovascular disease prediction. Low-level chronic inflammation appears to be involved with several types of cancer such as kidney, prostate, ovarian, and colorectal. With Alzheimer’s disease, chronic low-level inflammation has been linked to cognitive decline. IBD (inflammatory bowel disease) is a group of chronic inflammatory disorders of the digestive tract.

In terms of oral health, if gingivitis is not treated, it may progress to periodontitis. Periodontitis is triggered by an imbalance between resident subgingival microbiota and the host’s inflammatory response. For oral-systemic considerations, inflamed tissue and ulcerated subgingival pockets provide a bacterial port of entry to the circulation.

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Inflammation is the body’s response to bacteria or bacteremia, and periodontal disease increases the body’s burden of inflammation. When the immune cells experience acute inflammation, they make a mad dash to begin the healing process by attacking whatever irritant or microbial aggressor is there. With periodontal disease, the inflammation is chronic, which sets the stage for a low-grade inflammatory process that may contribute to some systemic diseases such as cardiovascular disease, cancer, and even type 2 diabetes.^4-6

Inflammation 101

To understand relationships between oral health and systemic health, we should know some basics about the inflammatory process. Inflammatory response is an early host response that not only eliminates infectious agents and damaged tissue but also identifies them. The goal of that process is to bring the tissue back to homeostasis and resolution.

The five cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. If a person has a cut, bronchitis, or physical trauma, one or all the cardinal signs can develop. This is called innate immunity.⁷ Innate immune system activation results in inflammation, and this is first carried out by sentinel cells. Some that enter the fight are macrophages, natural killer cells, monocytes, neutrophils, and dendritic cells.

Unfortunately, with many diseases, inflammation doesn’t settle but becomes chronic, such as with arthritis, lupus, asthma, and periodontitis. With periodontal disease, the inflammatory response becomes chronic and can also be associated, directly or indirectly, with a host of systemic diseases and perhaps can even be causal to some.

There are changes between gingivitis and periodontitis. The lymphocytes, B and T, release inflammatory and immune mediators, all while invading the periodontal tissues and altering the metabolism of the bone; that results in adaptive immunity.⁸This group includes IL-1 (interleukin-1), IL-6, IL-17, tumor necrosis factor (TNF), and enzymes such as matrix metalloproteinases (MMPs).^9-13

Although infection is a necessary condition for chronic periodontal disease to develop, as far as is known, infection alone is not sufficient for disease progression. The pathogens activate the acquired immune system, contributing to the progression of the inflammatory condition. As the immune response continues, serious damage happens to both soft and hard periodontal tissues.¹⁴Simply, it is the host response to the microbes that is responsible for the breakdown.

Inflammatory players

Tissue damage in periodontal disease evolves from an abundance and dysregulated production of a potpourri of inflammatory mediators and enzymes, such as cytokines, prostaglandins, and MMPs.

Cytokines are soluble proteins that are couriers of sorts, transmitting signals from one cell to another. They play an essential role in the progression of chronic periodontitis. They’re effective wound healers in lower numbers, but an excessive production of them leads to tissue damage. These helpers are secreted by different cell types such as neutrophils, monocytes, and macrophages. Inflammatory cytokines are associated with the onset and progression of inflammation. Chemokines are cytokines that induce cell migration to the site of the infection or injury—a little like a traffic cop moving leukocytes and others into endothelial and epithelial cells. There are also anti-inflammatory cytokines whose job it is to control the proinflammatory cytokine response like IL-10. This balancing act is quite complex.

The expression of MMP-8 is induced and is upregulated by different inflammatory cytokines such as Iβ and TNFα. MMP-8 is the most plentiful of matrix metalloproteinases in diseased periodontal tissue, oral fluid, and gingiva. It accounts for 80% of total collagenases protein in gingival crevicular fluid (GCF). During periodontal disease, several inflammatory cells, such as neutrophils and macrophages, secrete MMP-8, and in high concentrations are involved with tissue destruction.¹⁵Elevated levels of MMP-8 can be found in a simple salivary diagnostic test and could be a potential help in the diagnosis of periodontal disease.

Prostaglandins are found in the plasma membrane of most cells. They control processes such as inflammation, blood flow, and the formation of blood clots, and can induce labor. As prostaglandins E2 (PGE 2) increase, so does the severity of periodontal disease. It is known to have an activity on fibroblasts and osteoclasts and induce the synthesis of MMPs, IL-1ß, and other cytokines.¹⁶ PGE 2 has a significant role in contributing to tissue damage in periodontitis, and elevated levels have been found in the GCF in patients with juvenile periodontitis and those who have developed peri-implantitis.

As research emerges in the relationship between oral and systemic health, inflammation reduction seems to be the key. It is a balance between the inflammatory mediators that amplify and those that promote the return to homeostasis. To help our patients return to homeostasis, our target in periodontal therapy—surgical or nonsurgical—is to reduce the elements that may cause inflammation. Therapies may include scaling and root planing, probiotics, ozone or laser therapy, increasing antioxidants, behavior modifications, and perhaps the limited use of antibiotics.

Editor's note: This article appeared in the October 2022 print edition of RDH magazine. Dental hygienists in North America are eligible for a complimentary print subscription. Sign up here.

References

1. Van Dyke TE, Kornman KS. Inflammation and factors that may regulate inflammatory response. J Periodontol. 2008;79(8 Suppl):1503-1507. doi:10.1902/jop.2008.080239

2. Medzhitov R. Inflammation 2010: new adventures of an old flame. Cell. 2010;140(6):771-776. doi:10.1016/j.cell.2010.03.006

3. Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol. 2008;8(5):349-361. doi:10.1038/nri2294

4. Sanz M, Marco Del Castillo A, Jepsen S, et al. Periodontitis and cardiovascular diseases: Consensus report. J Clin Periodontol. 2020;47(3):268-288. doi:10.1111/jcpe.13189

5. Nwizu N, Wactawski-Wende J, Genco RJ. Periodontal disease and cancer: epidemiologic studies and possible mechanisms. Periodontol 2000. 2020;83(1):213-233. doi:10.1111/prd.12329

6. Preshaw PM, Alba AL, Herrera D, et al. Periodontitis and diabetes: a two-way relationship. Diabetologia. 2012;55(1):21-31. doi:10.1007/s00125-011-2342-y

7. Carrillo JLM, Rodríguez FPC, Coronado OG, García MAM, Cordero JFC. Physiology and pathology of innate immune response against pathogens. Physiology and Pathology of Immunology. doi:10.5772/intechopen.70556
8. Hajishengallis G, Korostoff JM. Revisiting the Page & Schroeder model: the good, the bad and the unknowns in the periodontal host response 40 years later. Periodontol 2000. 2017;75(1):116-151. doi:10.1111/prd.12181
9. Franco C, Patricia HR, Timo S, Claudia B, Marcela H. Matrix metalloproteinases as regulators of periodontal inflammation. Int J Mol Sci. 2017;18(2):440. doi:10.3390/ijms18020440
10. Björnfot Holmström S, Clark R, Zwicker S, et al. Gingival tissue inflammation promotes increased matrix metalloproteinase-12 production by CD200R^lowmonocyte-derived cells in periodontitis. J Immunol. 2017;199(12):4023-4035. doi:10.4049/jimmunol.1700672
11. Nascimento GG, Leite FRM, Scheutz F, López R. Periodontitis: from infection to inflammation. Curr Oral Health Rep. 2017;4(4):301-308. doi:10.1007/s40496-017-0158-
12. Dahlen G, Basic A, Bylund J. Importance of virulence factors for the persistence of oral bacteria in the inflamed gingival crevice and in the pathogenesis of periodontal disease. J Clin Med. 2019;8(9):1339. doi:10.3390/jcm8091339
13. Cecoro G, Annunziata M, Iuorio MT, Nastri L, Guida L. Periodontitis, low-grade inflammation and systemic health: a scoping review. Medicina (Kaunas). 2020;56(6):272. doi:10.3390/medicina56060272
14. Ramadan DE, Hariyani N, Indrawati R, Ridwan RD, Diyatri I. Cytokines and chemokines in periodontitis. Eur J Dent. 2020;14(3):483-495. doi:10.1055/s-0040-1712718
15. Kraft-Neumärker M, Lorenz K, Koch R, et al. Full-mouth profile of active MMP-8 in periodontitis patients. J Periodontal Res. 2012;47(1):121-128. doi:10.1111/j.1600-0765.2011.01416.x

16. Kardeşler L, Buduneli N, Biyikoğlu B, Cetinkalp S, Kütükçüler N. Gingival crevicular fluid PGE2, IL-1beta, t-PA, PAI-2 levels in type 2 diabetes and relationship with periodontal disease. Clin Biochem. 2008;41(10-11):863-868. doi:10.1016/j.clinbiochem.2008.04.013