E2 ◊Page E1 HYGIENE TRIBUNE Dental Tribune Middle East & Africa Edition | 2/2020 braking signal for neutrophils.14 As- pirin transforms lipoxin into a more bioactive form with more powerful pro-resolving properties.18 Resolvins Resolvins are substances derived from omega-3 dietary fatty acids. Several clinical studies have shown that diets rich in omega-3 are use- ful in the prevention and treatment of arthritis, cardiovascular disease (CVD) and other inflammatory con- ditions. Resolvins formed from omega-3 may be responsible for this.17 Re- solvins act locally to stop neutrophil recruitment and infiltration. Neutro- phils are present in inflamed or in- jured tissue, and their effective elim- ination is a prerequisite for complete resolution of the inflammatory re- sponse and return to homeostasis.19 Results from P. gingivalis-induced periodontitis animal studies showed topical resolvin treatment stopped the progression of periodontal dis- ease.20 Silk threads were tied around rabbit teeth to trap bacteria, and then P. gingivalis was added to induce per- iodontitis. One group received topi- cal application of resolvin, the other group received a placebo. The rabbits that received the topical resolvin re- mained healthy; the placebo group developed periodontal disease. Topi- cal resolvin treatment stopped the progression of disease, and there was complete resolution of periodontal inflammation. Treatment resulted in bone regrowth to pre-disease lev- els. Histological evidence showed both new collagen and new bone deposition.20 The chronic maladaptive inflammatory response The primary aetiological basis for periodontal disease is bacterial. How- ever, the excessive host inflamma- tory response and inadequate reso- lution of inflammation are critical to the pathogenesis of periodontitis.18 Periodontal disease results from the body’s failure to turn off its inflam- matory response to infection. The result is chronic maladaptive inflam- mation.17 As discussed, keystone pathogens, such as P. gingivalis, create a dys- biosis between the host and dental plaque. An essential step in the in- nate mechanism is impaired, lead- ing to growth in the number of commensal bacteria and increased inflammation. This produces an en- vironment that exudes a rich source of nutrients, such as degraded host proteins, which are exactly what P. gingivalis needs for survival and growth. P. gingivalis continues to exploit the environmental change, leading to more bacteria, even higher inflammation and bone re- sorption, and a perfect niche space (deeper periodontal pockets) where all the processes can continue undis- turbed.9 Chronic periodontitis has multiple aetiologies. The persistent bacterial infection of P. gingivalis is just one of these. Inflammatory disease repre- sents a disruption of tissue homeo- stasis. Any factor (whether microbial or host-based) that can destabilise the homeostatic equilibrium can tip the balance towards inflamma- tory disease.8 Acute inflammation that is resolved within a reasonable time frame prevents tissue injury. Inadequate resolution and failure to return to homeostasis result in chronic inflammation and tissue de- struction.18 In chronic, unresolved inflamma- tion, the following applies: 1. Cellular and molecular respons- es to bacterial challenges involve constant adjustment and regula- tory feedback.21 2. Neutrophils, macrophages and monocytes continue to secrete cytokines. This creates a complex chronic lesion that destroys the periodontium. 3. Cytokines promote the release of matrix metalloproteinases (MMPs). (MMPs are proteolytic en- zymes implicated in normal bone remodeling. They include colla- genases. Virtually all collagenases found in periodontal disease are derived from host cells and not from bacteria.21 They are also the key mediators in irreversible tis- sue destruction in periodontitis and have been used as biomarkers of disease progression. 22) 4. Tissue destruction is not uni- directional. It is constantly being adjusted by host–bacteria interac- tions.21 5. Alveolar bone destruction is the result of the uncoupling of the normally tightly coupled pro- cesses of bone resorption and for- mation.21 6. Prostaglandin production plays a role in alveolar bone resorption. Cytokines are an intermediate mechanism between bacterial stim- ulation and tissue destruction. They were historically identified as leu- kocyte products, but many are also produced by other cell types, such as fibroblasts and osteoblasts.23 The balance between stimulatory and inhibitory cytokines, and the regula- tion and signalling of their receptors, may determine the level of peri- odontal tissue loss.23 The host response is the major con- tributing factor to chronic maladap- tive periodontal disease. A deficient host response initiates the chronic condition, and a too vigorous re- sponse leads to further tissue break- down.23 Risk factors for periodontal disease Clinical observation has shown re- markable variations in host respons- es between individuals and in their presentation of periodontal disease. Though microbial challenge is a primary initiating factor, there are many other variables that modify disease expression. These risk fac- tors interfere with the way the body responds to bacterial invasion. With- out the risk factors, the host may be capable of limiting periodontal tis- sue destruction. Disease modifiers, such as smoking, in the presence of bacterial accumulation may shift the immune response beyond normal parameters.24 Bacteria initiate perio- dontitis. They are essential, but they are insufficient. What is required is a susceptible host. Risk factors deter- mine disease susceptibility, onset, progression, severity and outcome.21 Through the 1990s, studies were undertaken to establish specific risk factors for periodontal disease. Clini- cal presentation, expected progres- sion and responses to therapy were found to be “a net integration of the host response modified by patient genetics and environmental factors”. These factors may shift the balance to more severe periodontal destruc- tion.24 The various environmental, acquired and inherited risk factors were found to be diabetes, smoking, poor oral hygiene, specific microflo- ra, stress, race and sex.25 Diabetes increases risk through an amplified inflammatory response and depressed wound healing.26 Dia- betics have cytokines that respond to the bacterial challenge at a higher ÿPage E3 Fig. 2: The active resolution of the acute response. Periodontal tissue: The stimulus (bacteria) is removed. Cellular level: The cre- vicular fluid contains fewer, weakened neutrophils and remnants of bacteria. Biochemical level: Arachidonic acid produces lipoxins. Dietary omega-3 produces resolvins. Lipoxins and resolvins ac- tively stop inflammation. Fig. 3: Return to health. foreign substances. These immune cells also release chemical mediators called cytokines that assist antibod- ies in clearing pathogens or marking them for destruction by other cells. The innate response is non-specific.1 The adaptive response is specific. Pathogens are recognised so that a stronger response will occur should these pathogens return in the future. The adaptive response is tailored to remove specific pathogens and to re- member the pathogen’s antigen sig- nature. T cells recognise foreign anti- gens and specifically target them. B cells produce antibodies against the antigen, and they assist the phago- cytic cells in mounting a response to the noxious stimulus.1 In healthy periodontium, the in- nate response eliminates or neutral- ises foreign bodies, and is protective against injury or infection. The se- quence is as follows:11 1. There is vascular dilation, en- hanced permeability of capillaries, and increased blood flow. 2. Neutrophils (also known as pol- ymorphonuclear leukocytes) are dispatched to the site. 3. Macrophages and others are re- cruited to the site. 4. Cell mediators (cytokines) are produced by these recruited im- mune cells and by local cells in the area, such as fibroblasts and osteoblasts. Cytokines are the mechanism the body uses for cell communication. They are biologi- cally active proteins that alter the function of the cell that releases it or the function of adjacent cells.12 They can act locally to regulate the inflammatory process or can be dispatched to distant sites.6 5. Chemokines (cytokines with chemotactic properties) are re- leased and play an important role in further leukocyte recruitment.13 6. These cytokines work with the body to defend it from attack. The immune cells and their secreted chemicals attempt to destroy, dilute or wall off the injurious agent.12 7. T and B cells mediate the adap- tive response. It is noteworthy that, although oral bacteria live close to a highly vascu- larised periodontium, very few bac- teria cause systemic infections in a healthy individual. This is the result of the highly efficient innate host de- fence system that monitors bacterial growth and prevents bacterial intru- sion into the local tissue. Dynamic equilibrium (homeostasis) exists be- tween the dental plaque bacteria and the innate host defence system.7 This is the situation as it occurs in health. When there is a compromise in the health of the individual, systemically or locally, the process of inflamma- tory disease begins. Resolution of the inflammatory response Complete resolution of an acute in- flammatory response and the body’s return to homeostasis is necessary for health. The leukocytes and in- vading bacteria must be removed without leaving remnants of the conflict.14 In the past, it was thought that the innate response peters out passively as the pro-inflammatory signals decline.15 However, evidence now suggests that the resolution of inflammation and return to homeo- stasis is an actively regulated process, not a passive one.16 There are special- ised pro-resolving lipid mediators in chemically distinct families that are involved in this process. These are lipoxins, resolvins and protectins. These substances are actively bio- synthesised during the resolution phase of acute inflammation and act to control the magnitude and dura- tion of inflammation.11 Lipoxins At the end of healthy inflamma- tion, neutrophils stop secreting pro-inflammatory cytokines and begin synthesising compounds that actively halt inflammation. These compounds are called lipoxins. They are derived from lipids (arachidonic acid, a fatty acid found in cell mem- branes) released from neutrophils and other inflammatory cells.17 Dur- ing acute inflammation, arachidonic acid is converted to pro-inflammato- ry mediators, including prostaglan- din. In the healthy individual, the elevated prostaglandin level signals the need to resolve inflammation. This triggers a switch in the action of arachidonic acid to now produce lipoxins.17 Lipoxins are essentially a Fig. 4: Early chronic lesion. Periodontal tissue: Increased plaque, breakdown of the periodontal ligament and ulceration of the epi- thelial lining; start of bone resorption. Cellular level: An increased number of neutrophils, macro phages and others. Biochemical level: Increased pro-inflammatory cytokine activity; arachidonic acid continues to produce prostaglandin; release of MMPs. Fig. 5: Late chronic lesion. Periodontal tissue: Apical migration of pathogenic bacteria, such as P. gingivalis, further breakdown of the periodontal ligament and increased ulceration of the epithe- lial lining; severe bone resorption. Cellular level: More neutrophils, macrophages, etc. Biochemical level: Increased pro-inflammatory cytokines regulate release of MMPs (involved in bone resorption and collagen degradation). Collagen fragments provide nutrition