*5.1.3 Tumor necrosis factor alpha*

TNF-α is a molecularly distinct cytokine and a key inflammatory mediator in periodontal disease that shares many biologic activities with IL-1β [92]. Tumor necrosis factor alpha is a multi-effect cytokine that has many functions, from cell migration to tissue destruction. Tumor necrosis factor alpha impacts cell migration by inducing the upregulation of adhesion molecules and adhesion of neutrophils to the vessel wall, leading to extravasation. It also stimulates the production of chemokines involved in cell migration to infected and inflamed sites [93–96]. The proinflammatory effects of TNF-α include the stimulation of endothelial cells to express selectins that facilitate the leukocyte recruitment, the activation of macrophage IL-1β production, and the induction of PGE2 by macrophages and gingival fibroblasts [97].

#### **5.2 Lipid mediators of inflammation-prostaglandins and thromboxanes**

Prostaglandins are derived from the hydrolysis of membrane phospholipids. Prostaglandin E2 (PGE2) and thromboxane B2 are lipid molecules produced by many host cells through the cyclooxygenase pathway, one of the two major paths of arachidonic acid metabolism. Inflamed gingiva synthesizes significantly larger amounts of prostaglandins when incubated with arachidonic acid than in healthy gingiva [98]. Within gingival lesions, prostaglandin E2 is mainly localized to macrophage-like cells and is secreted when stimulated with bacterial lipopolysaccharide [99].

PGE2 induces the secretion of MMPs, as well as osteoclastic bone resorption, and it contributes significantly to the alveolar bone loss seen with all forms of periodontitis [100]. Prostaglandin E2 has biphasic actions on immune function. In high doses, it decreases the levels of IgG, but at low doses it has the potential to increase IgG. When combined with interleukin-4, low doses of prostaglandin E2 induce a synergistic rise in IgG production, suggesting an immune-regulatory role for prostaglandin E2 [101].

#### **5.3 Matrix metalloproteinase**

Matrix metalloproteinases are a family of structurally related, but genetically distinct, enzymes that degrade extracellular matrix and basement membrane components [102]. MMPs secreted by the majority of cell types in the periodontium, including fibroblasts, keratinocytes, endothelial cells, osteoclasts, neutrophils, and macrophages, are capable of degrading extracellular matrix molecules, including collagens [103, 104].

Most MMP activity in the periodontal tissues is derived from infiltrating inflammatory cells. In inflamed periodontal tissues, excessive quantities of MMPs are secreted by resident cells and neutrophils, resulting in the breakdown of the connective tissue matrix [105, 106] and leading to the development of collagendepleted areas within the connective tissues. The predominant MMPs in periodontitis, MMP-8 and MMP-9, secreted by neutrophils [107] are effective in degrading type 1 collagen, which is the most abundant collagen type in the periodontal ligament [108].

Matrix metalloproteinase activity is controlled by changes in the delicate balance between the expression and synthesis of matrix metalloproteinases and their major endogenous inhibitors, tissue inhibitors of matrix metalloproteinases [102]. The prolonged and excessive release of large quantities of MMPs in the periodontium leads to the significant breakdown of structural components of the connective tissues, thereby contributing to the clinical signs of disease. In periodontal disease, secretion of specific matrix metalloproteinases is stimulated or downregulated by various cytokines. The main stimulatory cytokines for matrix metalloproteinases are tumor necrosis factor alpha, interleukin-1, and interleukin-6 [109].

#### **6. Discussion**

The immune and inflammatory processes that result from periodontal inflammation in response to bacterial biofilm are complex and mediated by a large number of proinflammatory and anti-inflammatory cytokines and enzymes that function as a network of mediators. Many studies have confirmed that immune cells from patients with periodontal disease secrete higher quantities of proinflammatory cytokines than do cells from persons who are periodontally healthy [72]. These findings led to the concept of the "hyperinflammatory" or "hyperresponsive" trait in which certain individuals possess a hyperinflammatory phenotype that accounts for their increased susceptibility to chronic inflammatory conditions such as periodontitis [110].

Although plaque bacteria initiate the inflammatory response, most of the tissue damage results from the host response, which is influenced by genetic factors, as well as environmental and acquired risk factors [111]. An essential goal of interventions in inflammatory disease is the return of tissue to homeostasis, by rapid elimination of invading leukocytes from a disease site [112].

**21**

*Pathogenesis of Gingivitis*

all forms of periodontitis.

periodontitis.

**7. Conclusion**

disease.

destruction.

None.

Nil.

**Conflict of interest**

**Notes/thanks/other declarations**

*DOI: http://dx.doi.org/10.5772/intechopen.91614*

Inadequate resolution of inflammation and failure to return tissue to homeostasis result in neutrophil-mediated destruction and chronic inflammation [113], with destruction of both extracellular matrix and bone [114] leading to advanced

Recently efforts are undergoing to control inflammation by the use of pharmacologic agents that inhibit proinflammatory mediator pathways (e.g., nonsteroidal anti-inflammatory drugs) [115] which target cyclooxygenase 1-dependent and cyclooxygenase 2-dependent pathways, inhibiting the generation of prostanoids. Accordingly, there is a need for the development of adjunctive agents for the management of periodontitis based on the current understanding of the etiology and pathobiology of periodontal disease. Host modulation therapy is an important emerging treatment strategy for managing

Periodontal diseases (gingivitis and periodontitis) are inflammatory diseases in which microbial etiologic factors induce a series of host responses that mediate inflammatory events. The maintenance of a healthy mucosal system is characterized by a continuous coordinated network of immune response that maintains the integrity of the tissue. Persistence of bacterial infection results in cellular and molecular modifications of the host response resulting in clinical manifestations of

The presence of increased inflammation due to persistence of microbial pathogens with a failure of innate immunity systems will cause the shift of disease to a chronic state, later progressing to bone loss and periodontal tissue destruction. Even though persistent gingivitis is a risk factor for periodontal attachment loss, periodontitis is always a successor of gingivitis. However, studies in the last decade have brought significant understanding of the pathogenesis of periodontal disease by the recognition of dental plaque as a biofilm, discovery of new diseaseassociated bacterial species, the role of risk factors in disease susceptibility, and advanced host-derived cellular and molecular mechanisms in periodontal

#### *Pathogenesis of Gingivitis DOI: http://dx.doi.org/10.5772/intechopen.91614*

Inadequate resolution of inflammation and failure to return tissue to homeostasis result in neutrophil-mediated destruction and chronic inflammation [113], with destruction of both extracellular matrix and bone [114] leading to advanced periodontitis.

Recently efforts are undergoing to control inflammation by the use of pharmacologic agents that inhibit proinflammatory mediator pathways (e.g., nonsteroidal anti-inflammatory drugs) [115] which target cyclooxygenase 1-dependent and cyclooxygenase 2-dependent pathways, inhibiting the generation of prostanoids. Accordingly, there is a need for the development of adjunctive agents for the management of periodontitis based on the current understanding of the etiology and pathobiology of periodontal disease. Host modulation therapy is an important emerging treatment strategy for managing all forms of periodontitis.
