Pathogenesis mechanisms in gingival inflammation
Pathogenesis mechanisms in gingival inflammationAll forms of PD diseases initiated by factors produced by MO that injure the host tissue (direct path)
Or activate endogenous inflammatory system that secondarily affect the integrity of periodontium (indirect path)
Exogenous mediators- Direct injury by plaque MO
MO invade into soft tissue, then multiply & produce noxious substances such as spirochetes in NUG, A.a. during localized aggressive periodontitis (LAP). Such substances will damage tissue diectly, like:• 1. Hydrolytic enzymes attack substrate as collagen, elastin, fibronectin, fibrin & other components of inter-cellular (i.c.) matrix of epithelium & CT
• 2. Metabolic products: ammonia, indole, H2S, butyric acid
• 3. Specific substances such as leukotoxin that destroy Leukocytes & substances that activate T-suppressor cells
Exogenous mediators- Direct injury by plaque MO
• 4. Factors that depress fibroblasts, endothelial &• epithelial cells proliferation that adverse the capacity to
• respond to irritant
• 5. Lipopolysacharides (endotoxins) of G-ve:
• A. Stimulate B-Lymphocytes proliferation & AB production (mitogenic effect)
• B. Stimulate macrophages to secrete neutral proteases (NP)
• C. Promote osteoclast bone resorption
• D. Trigger complement system by alternative path
Exogenous mediators- Direct injury by plaque MO
• 6. Lipoteichoic acid (LTA) from G+ve bacteria: activates endogenous mediators of vascular permeability & encourage inflammatory cells to move into tissues & to discharge pro-inflammatory agentsExogenous mediators- Direct injury by plaque MO
• 7. Currently interest in specific molecules is increased,• particularly molecules from P. gingivalis, which may
• be capable of generating a strong immunological
• reaction.These so called immuno-dominant molecules include:Arginine (Arg)1-protease, Fimbrillin (types I and II), Heat Shock Proteins and various other surface antigens thought to be capable of inducing an excessive antibody response.
Endogenous mediators
Endogenous mediators of inflammationIdentified in gingival exudate & one may have control
• over an extent such as vasoactive amine which is
• responsible for immediate but transient change in
• vascular permeability, while prostaglandin & kinin are
• responsible for delayed & sustained phase of plasma
• protein leakage
The mediators linked to one another via feed back
mechanism that amplify their biological properties
Have more than one function & after released rapidly
inactivated in local areas (proteases & proteases
inhibitors)
Vasoactive amine
Histamine found in and secreted by mast cells, basophiles & plateletsMast cells widely distributed in connective tissues adjacent to small blood vessels & their no. increase with long standing gingival lesions
Mast cells also secrete serotonin, heparin, lysozymal enzymes, proteases, arachidonic acid (A.A.), bradykinin
Kinin system
Kinin system: (Kallikrein-Kinin system) Kinins are peptides produced as a consequence of proteolytic action of Kallikreins (serine proteases) that present in plasma & inflammatory exudateActivated by clotting factor12 (hageman factor) that activated following contact with various surfaces (Collagen, vascular basement membrane)
Kallikreins interact with their protein substrate (kinenogen) leading to its cleavage & liberation of kinin
Most effective one is bradykinin
Pharmacological effects• Vascular smooth muscle relaxation & contraction
• 2. Increases vascular permeability
• 3. Leukocytes emigration
• 4. Pain initiation
It affects on blood vessels indirectly by triggering the A.A. (acid) metabolism
Bacteria & neutral proteases activate kinin system
Complement system
Consist of about 30 membrane-associated cell receptors & soluble serum glycoproteins, organized into 9 components
• Synthesized in: liver, small intestine & macrophages
Complement Activation: is a sequence of cascading type pathway as after one component binds by the fc portion of AB in AG-AB complex, another component reacts in an order sequence
Each activated component cleaves the next reacting member of the series into fragment until the cascade completed
Complement system
Activation takes 1 of 2 paths: classical & alternative pathClassical path by immune complex & certain membranes with a sequence of C1…C9
Alternative path by endotoxin, NP/occur by direct activation of 3rd complement (C3), it occurs in most PD pocket & classical path occasionally occur
C activation induces host or bacterial cells damage by membrane attack complex (C56789), that bound with phospholipids layer of cell membrane leading to formation of ion channels that induce change in permeability which cause osmotic lyses
Complement system
Some MO resist this lyses by means such as thick peptidoglycan layer in G+ve that protect inner membraneC3 most important complement & predominant accounting for one 3rd of total C.
C system is a central component of inflammation that enables Lymphocytes to recognize & bind foreign substances for which they lack receptors
Complement system
1. Vasoactive (kinin like C2a) induce pain, increase vascular permeability & dilation2. Anaphylatoxins C3a & C5a, produce anaphylaxis by inducing mast cell secretion
3. Chemotaxin C5a: attracts Lymphocytes & stimulates phagocyte secretion
4. Opsonin C3b: bound to AG to enable phagocytes to ingest them (AG)
5. In addition, complements induce bone resorption & lymphokine production (C3b)
In summary:
C system enable Lymphocytes to ‘see’ & ‘find’ the problem
(foreign body), facilitate its phagocytosis & destruction
or direct the destruction of cells or MO via membrane attack complex
Arachidonic Acid
A.A. is a fatty acid found in the plasma membrane of most cells
Activation of phospholipase A2 in PNL & macrophages will release A.A. from membrane phospholipid, while in mast cells & platelets A.A. hydrolysed by phospholipase C
Corticosteroids inhibit phospholipase enzyme
Arachidonic acid metabolites (prostaglandin & leukotrein)
Cyclooxygenase catalyzes A.A into prostaglandin
lipooxygenase catalyzes A.A into leukotriene
NSAID inhibit cyclooxygenase
A.A. maybe non-enzymatically converted by O2-derived mediator into chemotactic acid
Prostaglandins
The pro-inflammatory cytokines are capable of inducing macrophages and other cells to produce copious amounts of prostaglandins, particularly PGE2 which are potent vasodilators and inducers of cytokine production by various cellsPGE2 acts on fibroblasts and osteoclasts, together with cytokines, to induce MMP production, which is relevant to tissue turnover and in the destructive process in periodontitis
Elevated levels of PGE2 in inflamed G tissue & G fluid especially from PD site exhibiting recent localized aggressive periodontitis (LAP), so its indicator of disease activity
PGE2 appears to be partly responsible for bone loss that can be reduced by NSAID
ProstaglandinsSo the roles of prostaglandins:
1. Increase vascular permeability
2. Modulate T-Lymphocyte function
3. Osteoclast bone resorption
Leukotrienes
Leukotrienes are a family of eicosanoid inflammatory mediators produced in leukocytes by the oxidation of A.A. and the essential fatty acid EPA (eicosapentaenoic acid) by the enzyme arachidonate 5-lipoxygenase
Functions:
1. Increase vascular permeability
2. Promote aggregation of PNL
3. Stimulate chemotaxis
4. PNL degranulation & phagocytosis
5. Decrease T-Lymphocytes proliferation & lymphokines production
O2 derived metabolites
Increased O2 consumption in PNL & macrophages upon contact with bacteria, immune complex & complements, is related to activated oxidase enzyme which present in the cell membrane, which will trap & reduce O2 in a series of steps to yield radicals (free radicals)Such as:
Superoxide anion (O2ˉ)
hydrogen peroxide (H2O2)hydroxyl radical (OHˉ)
They have microbiocidal activity & H2O2 is an important one
O2 derived metabolitesMyeloperoxidase react with H2O2 to yield a complex that will oxidize chloride (Cl) to yield hypochlorous acid (HClO) which is more potent than H2O2 that oxidize bacterial surface and lead to cell lyses
Inherited deficiency of oxidase lead to P.D. & stomatitis as in chronic granulomatous disease
Potential roles of O2 metabolites (radicals):
1. Killing &/ inducing auto destruction (apoptosis or suicide) of MO
2. Damaging surrounding normal cells
3. Destruction of tumor cells
4. Depolymerization of structural matrix of tissue (proteoglycan)
5. Oxidation of A.A.to produce chemotactic factors
6. Suppression of protease inhibiter system
Neutral proteases
Elastase, Collagenase, Cathepsin GReleased by PNL & macrophage
Functions:
1. Destruction of CT
2. Digestion of G+ve & G-ve bacteria
3. Digestion of AB
4. Activation of alternative complement path
5. Stimulate B-Lymphocytes proliferation & AB production
6. Generation of kinin-like peptides from kininogen
7. Vascular permeability
Matrix metalloproteinases
Extracellular matrix components including collagen (tropocollagen), proteoglycans and other proteins (elastin, fibronectin, laminin, osteocalcin, osteopontin, bone sialoprotein, osteonectin and tenascins)All of these matrix components are constantly in a state of turnover and thus there is much matrix enzyme activity in both health & disease, and tissue repair & remodeling
Matrix metalloproteinases (MMP) are responsible for remodeling and degradation of matrix components. MMPs also degrade interstitial and basement membrane collagens, fibronectin, elastin, laminin, and the proteoglycan core protein
Matrix metalloproteinases
MMPs are found in a pro-enzyme form, and their activation is extracellular
One of the MMPs receiving much attention is the neutrophil (PMN) collagenase which is found in higher concentrations in inflamed gingival specimens than in clinically healthy gingivae
It has been shown that gingival biopsies taken from patients with periodontal disease indicated the presence of the enzyme, whereas gingival specimens obtained from treated subjects had no enzyme present.
Matrix metalloproteinases
The increased presence of these MMP enzymes in diseased over healthy sites, their increase during experimental gingivitis and decrease after periodontal treatment suggest that MMPs are involved in periodontal tissue breakdownAmong the MMPs both PMN collagenase and fibroblast collagenase have the unique ability of cleaving the triple helix of type I, II and III collagens, thus initiating extracellular matrix degradation which is not shared by the other members of the family
Cytokines
Chemokines, lymphokines, cytokines, interleukinsCytokines are soluble proteins, secreted by cells,which act as messenger molecules that transmit signals to other cells
They have numerous actions which include initiation and maintenance of immune and inflammatory responses and regulation of growth and differentiation of cells
The interleukins are important members of the cytokine group and are primarily involved in communication between leukocytes and other cells, such as epithelia, endothelia and fibroblasts
Involved in both immune and inflammatory processes
Cytokines
These molecules are released in small amounts and have a variety of actions on cells which carry the specific receptor for the particular interleukinPro-inflammatory cytokines:
Cytokines such as interleukin IL-1a, IL-1β and tumor necrosis factor TNF-α stimulate bone resorption and inhibit bone formation. IL-1 can act on the fibroblasts to promote cellular matrix repair or destruction
Cytokines
Molecules act to recruit defense cells to areas where they are needed and are important in cell mediated responses. The term chemokine is used to describe these molecules and is an abridged form of the term "chemotactic cytokine“Chemotactic cytokines: A series of more than 20 molecules have been identified, among which the most famous is interleukin 8 (IL-8)
IL-8 has a powerful chemotactic function for leukocytes particularly for neutrophils but also for lymphocytes and macrophages
Cytokines
Lymphocyte signaling cytokines:T-helper cells are lymphocytes within the tissues which regulate both the humoral and cell mediated immune responses via cytokines
The humoral immune response is promoted by T-helper cell type 2 (TH-2) which produces characteristic cytokines namely IL-4, IL-5, IL-10 and IL-13
The TH-1 lymphocytes release IL-2 and interferon IFN-γ which enhance cell mediated responses
These cytokines provide a precise mechanism for the control of the immune response so that a sufficient response is produced to deal with the offending pathogen