Nonspecific Mediators of Periradicular Lesions
Nonspecific mediators can be classified into following types:
1. Cell derived mediators:
– Neuropeptides
– Eicosanoids/arachidonic acid derivatives – Cytokines
– Lysosomal enzymes
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– Platelet activating factor – Vasoactive amines – Prostaglandins 2. Plasma derived mediators
– The fibrinolytic system – The complement system – The kinin system
3. Extracellular matrix derived mediators – Effector molecules
Cell Derived Mediators (Fig. 5.10)
1 . Neuropeptides: These are generated following tissue injury by the somatosensory and autonomic nerve fibers.
Neuropeptides include:
– Substance P (SP): Causes vasodilation, increased vascular permeability and increased blood flow.
– Calcitonin-gene related peptide (CGRP): results in vasodilation.
2. Eicosanoids: The injury to cells results in release membrane phospholipid, arachidonic acid which is metabolized by either cyclooxygenase pathway or lipoxygenase pathway to form prostaglandins (PGs) or leukotrienes (LTs) respectively, which are involved in inflammatory process.
a. Prostaglandins are of various types:
– PGE2, – PGD2, – PGF2a, – PGI2
In cases of acute apical periodontitis and areas of bone resorption, PGE2 and PGI2 are commonly observed.
Action of PGs can be inhibited by administration of indomethacin which inhibits the enzyme cyclooxygenase thus inhibiting formation of prostaglandins.
b. Leukotrienes: These are produced by activation of lipoxygenase pathway of arachidonic acid metabolism.
Studies have shown the presence of LTB4, LTC4, LTD4 and LTE4 in periradicular lesions which cause different effects on the tissues as shown in (Fig. 5.11).
3. Cytokines – These are low molecular weight polypeptides secreted by activated structural and hematopoietic cells.
Different cytokines such as interleukins and tumor necrosis
factor (TNF) cause development and perpetuation of periradicular lesions.
They are of two types:
a. Proinflammatory cytokines – IL1 α and β, (Interleukins) – IL6 α and β, – IL8 α and β.
b. Chemotactic cytokines – TNFα (macrophage derived)
(Tumor necrosis factor) – TNFβ (T-lymphocyte derived)
– TNFγ.
a. Proinflammatory cytokines
IL1 – The local effects of IL1 are –
– Enhanced leukocyte adhesion to endothelial walls.
– Stimulate PMNLs and lymphocytes.
– Activates production of prostaglandins and proteolytic enzymes.
– Enhances bone resorption.
– Inhibits bone formation.
Fig. 5.10: Cell derived mediators
Fig. 5.11: Leukotrienes
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IL1 β is predominant in cases of periapical pathology.
IL6 – It is secreted by lymphoid and non-lymphoid cells and causes inflammation under the influence of IL1, TNF α and interferon γ (IFN). It is seen in periapical lesions.
IL8 – It is produced by macrophages and fibroblasts under the influence of IL1 β and TNF α and is associated with acute apical periodontitis.
b. Chemotactic cytokines
TNF – They are seen in chronic lesions associated with cytotoxic and debilitating effect. TNF α is seen in chronic apical lesions and root canal exudates.
1. Colony stimulating factor (CSF) – They are produced by osteoblasts and regulate the proliferation of PMNLs and preosteoclasts.
2. Growth factors (GF) – They are the proteins produced by normal and neoplastic that regulate the growth and differentiation of non- hematopoietic cells. They can transform a normal cells to neoplastic cells and are known as transforming growth factors (TGF).
They are of two types
-a. TGF α (produced by malignant cells) – not seen in periapical lesions.
b. TGF β (produced by normal cells and platelets).
They counter the adverse effects of inflammatory host response by:
– Activating macrophages.
– Proliferation of fibroblasts.
– Synthesis of connective tissue fibers and matrices.
Lysosomal Enzymes
Lysosomal enzymes such as alkaline phosphatase, lysozyme, peroxidases, collagenase cause increase in vascular permeability, leukocytic chemotaxis, bradykinin formation and activation of complement system.
Platelet Activating Factor
It is released from IgE—sensitized basophils or mast cells. Its action include increase in vascular permeability, chemotaxis, adhesion of leukocytes to endothelium and broncho-constriction.
Vasoactive Amines
Vasoactive amines such as histamine, serotonin are present in mast cells, basophils and platelets. Their release cause increase in tissue permeability, vasodilation used vascular permeability (Fig. 5.9).
Prostaglandins
These are produced by activation of cyclooxygenase pathway of arachidonic acid metabolism. Studies have shown high levels of PGE2 in periradicular lesions. Torbinejad et al found that periradicular bone resorption can be inhibited by administration of indomethacin, an antagonist of PGs. This indicates that prostaglandins are also involved in the pathogenesis of periradicular lesions.
Plasma Derived Mediators (Fig. 5.12)
1. The fibrinolytic system: The fibrinolytic system is activated by Hageman factor which causes activation of plasminogen.
This results in release of fibrinopeptides and fibrin degradation products which cause increase in vascular permeability and leukocytic chemotaxis.
2. The complement system: Trauma to periapex can result in activation of kinin system which in turn activates complement system. Several studies have shown elevated levels of kinins and C3 complement component in periradicular lesions. Products released from activated complement system cause swelling, pain and tissue destruction.
3. The kinin system: These are produced by proteolytic cleavage of kininogen. Release of kinins cause smooth muscle contraction, vasodilation and increase in vascular permeability (Fig. 5.13).
Effector Molecules
The inflammatory process causes not only the destruction of the cells but also the extracellular matrix in the periapical pathosis. The extracellular matrix is degraded by enzymatic effector molecules by various pathways like
• Osteoclast regulated pathway,
• Phagocyte regulated pathway,
• Plasminogen regulated pathway and
Fig. 5.13: Kinin system Fig. 5.12: Plasma derived mediators
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Histopathology of Periapical Tissue Response to Various Irritants
Root canal of teeth contains numerous irritants because of some pathologic changes in pulp. Penetration of these irritants from infected root canals into periapical area can lead to formation and perpetuation of periradicular lesions. In contrast to pulp, periradicular tissue have unlimited source of undifferentiated cells which can participate in inflammation and repair in inflammation and repair. Also these tissues have rich collateral blood supply and lymph drainage.
Depending upon severity of irritation, duration and host, response to periradicular pathosis may range from slight inflammation to extensive tissue destruction. Reactions involved are highly complex and are usually mediated by nonspecific and specific mediators of inflammation.
ENDODONTIC IMPLICATIONS (PATHOGENESIS