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  1. 1. Oral Infection and systemic diseases By Romissaa Aly Assistant lecturer of Oral Medicine, Periodontology, Diagnosis and Dental Radiology (Al-Azhar University)
  2. 2. The epithelium is a unique barrier that separates the body from its environment. The basic structure of the oral mucosa is similar to that of human skin. It consists of two layers: an epithelium with a basement membrane; and an underlying connective tissue (lamina propria) that includes the supra-alveolar fiber apparatus, blood, lymphatic vessels and nerves . Essential functions of oral mucosal barriers are resistance against pathogens, exogenous substances and mechanical stress .
  3. 3. The epithelium of the gingiva and papillae is a stratified squamous keratinized epithelium, whereas the oral sulcular epithelium is stratified squamous and nonkeratinized. The junctional epithelium is squamous and nonkeratinized and although it does not exhibit true phenotypic stratification, the outermost cells tend to be elongated and to lie with their long axis parallel to the tooth surface .
  4. 4. The gingival connective tissue consists of a dense network of collagen fibers that are able to provide firmness to the gingiva and to attach the gingiva to the underlying cementum and alveolar bone. The connective tissue of the gingiva is also rich in lymphatic and blood vessels, nerves and many cells specific to immune–inflammatory and vascular systems.
  5. 5. A characteristic feature of the epithelium is its exceptionally high rate of cellular turnover, which is much higher than in skin.  This high turnover rate provides an effective barrier to bacterial penetration.  The gingival epithelial turnover time was found to be 5–11 days in primates and 3–5 days in mice. The protective function of the gingival epithelium is also enhanced by saliva secretion, which physically lubricates the epithelial surfaces and
  6. 6. Cytokeratins are considered to be molecular markers for different types of epithelialdifferentiation. Gosselin et al. demonstrated that reconstituted gingival epithelium in vitro expressed some cytokeratins that are specific for embryonic, simple and tumor epithelia, whereas gingival epithelium reconstituted on a connective tissue equivalent expressed all cytokeratins present in the normal gingival tissue.
  7. 7. These results suggest that the culture of gingival keratinocytes on connective tissue equivalents enables them to mimic the physiological stages of differentiation .
  8. 8. The basal cells form the proliferating layer of the epithelium and attach to the lamina densa of the lamina basalis through hemidesmosomes. The spinous cell layersare specialized for cell–cell contacts by many desmosomes. Cell–cell contacts via gap junctions are also abundant.
  9. 9. Apoptosis is a suicidal program leading to the elimination of individual cells, whereas programmed cell death during epidermal development results in cornification of the keratinocytes that establish a tight barrier of dead cells protecting the organism from the environment.
  10. 10. Furthermore, the molecular signal-transduction pathways and regulatory mechanisms of apoptosis and cornification of keratinocytes are clearly different .
  11. 11. Epithelial tissues provide a barrier between the body and the environment, and keratinocytes form the first line of defence against bacterial challenge . Gingival keratinocytes are connected to each other by a variety of specialized transmembrane proteins .
  12. 12. Structural components of tight junctions consist of a large number of different proteins, such as occludin , occludin 1B , zonula occludens protein-1 , zonula occludens protein-2 and zonula occludens protein-3 , as well as members of the protein family of claudins .
  13. 13. Claudins have barrier properties and directly regulate the gate function as paracellular tight-junction channels. These structures have biophysical properties that are similar to those of traditional ion channels. Another property is that they also recruit occludin to tight junctions .
  14. 14. Adherens junctions are protein complexes that occur at cell–cell junctions in epithelial and endothelial tissues and are localized usually more basal than are tight junctions. An adherens junction is defined as a cell junction whose cytoplasmic face is linked to the actin cytoskeleton
  15. 15. Adherens junctions may appear as bands encircling the cell (zonula adherens) or as spots of attachment to the extracellular matrix (adhesion plaques). Adherens junctions are cell-to-cell adhesion sites in which classic cadherins function as cell adhesion molecules and where the actin-based cytoskeleton and several cytoplasmic components are assembled .
  16. 16. Adherens junctions are established via calcium- dependent hemophilic binding of the extracellular cadherin domains.
  17. 17. Gap junctions are aggregates of intercellular channels between adjacent cells that mediate reciprocal exchange of metabolites and ions of <1 kDa in molecular mass, including second messengers, such as cyclic adenosine monophosphate and Ca2+. These intercellular channels are formed by head-to-head docking of hexameric assemblies (connexons) of tetraspan integral membrane proteins, the connexins (Fig. 7) .
  18. 18. Connexins and innexins are universally used to promote intercellular interactions between cells in solid tissues and circulating elements of the blood, and show multiple levels of regulation. Genetic studies have shown that gap junctions are involved in a wide variety of functions in homeostasis, regulation, regeneration and development.
  19. 19. The dysfunction of gap junctions is believed to be associated with cancer development. The expression of connexin 43, one of the major connexins in oral epithelia, was investigated in rat tongue carcinoma. The results indicated that down-regulation of connexin 43 might be an early event during oral carcinogenesis, which could be a biomarker for early changes in oral malignant transformation .
  20. 20.  The set-up of the in vitro test system for transepithelial electrical resistance measurements is shown. A close correlation between the number of junctional strands and junctional tightness, as judged by transmural resistance values, was demonstrated. The correlation between tight junctions and the transepithelial electrical resistance was also shown in primary human gingival keratinocytes .
  21. 21. Among all microorganisms in the oral cavity, some periodontal pathogens (Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia and Treponema denticola) are able to induce inflammatory responses that lead to attachment loss and periodontal destruction. Porphyromonas gingivalis is an anaerobic gram-negative coccoid rod that exhibits a variety of virulence factors.
  22. 22. This microorganism is considered as one of the primary microbiological factors involved in the pathogenesis of periodontitis and has recently been described as a ‘keystone pathogen’. Some strains of P. gingivalis produce a number of proteolytic enzymes, such as gingipains, amino peptidases, invasins, cytotoxic substances, collagenases , lipopolysaccharide , outer membrane proteins, fimbriae and capsule proteins .
  23. 23. Porphyromonas gingivalis ATCC 33277, one of the best- characterized strains, expresses fimbriae , and is able to produce gingipains and to invade oral cells ; however, invasion of P. gingivalis ATCC 33277 can be inhibited by protease inhibitors. Fimbriated P. gingivalis strains are more effective in entering human dendritic cells than are fimbriae-deficient strains .
  24. 24. Cytokines and chemokines of the epithelial barrier in periodontal infection
  25. 25. Histological studies revealed that oral keratinocytes express a variety of proinflammatory cytokines and chemokines, including interleukin- 1alpha, interleukin-1beta, interleukin-6, interleukin-8 and tumor necrosis factor-alpha.
  26. 26. Interleukin-1, interleukin-8, interleukin-6 and tumor necrosis factor-alpha are essential in the developmentm of inflammatory reactions and are involved in both the local and the systemic immune response to bacterial antigens. Interleukin-8 is crucial in the local defense against micro-organisms because of its function as a chemokine directing neutrophil migration .
  27. 27. In a mouse model it was shown that overexpression of interleukin 1alpha caused a syndrome that possessed the cardinal features of periodontal disease, including epithelial proliferation and apical migration, loss of attachment and destruction of cementum and alveolar bone .
  28. 28. Interleukin-6 can act as a proinflammatory and anti inflammatory cytokine. It is secreted by T-cells and macrophages to stimulate immune responses during infection and tissue damage leading to inflammation.  Increased levels of interleukin- 6 were shown in the crevicular fluid of inflamed periodontal pockets compared with healthy sites
  29. 29. Interleukin-8 is also known as neutrophil chemotactic factor because of its functions. It induces chemotaxis in neutrophils and other granulocytes, causing them to migrate toward the site of infection (14, 15).  High levels of interleukin-8 were detected in crevicular fluid and gingival tissue from patients with periodontitis .
  30. 30. The significance of tumor necrosis factor-alpha in the development of periodontitis has been linked mainly to its ability to induce connective tissue destruction and bone resorption
  31. 31. Role of epithelial-derived matrix metalloproteinases in periodontal infection
  32. 32. Matrix metalloproteinases are zinc-dependent endopeptidases that are able to degrade all types of extracellular matrix proteins and can process a number of bioactive molecules. They are known to be involved in many important processes, such as cell proliferation, differentiation, migration and death, as well as in cell–cell interactions.
  33. 33. Matrix metalloproteinases 2 and 9 are both type IV collagenases that are capable of degrading denatured interstitial collagens, gelatins, laminin and fibronectin , elastin and basement membrane- zone-associated collagens type IV and type VII . In the oral cavity, the main source of type IV collagenases has been suggested to be polymorphonuclear granulocytes that migrate into the oral cavity through the gingival sulcus.
  34. 34. The alternative name for matrix metalloproteinase-3 is stromelysin-1, an enzyme that degrades collagen types II, III, IV, IX and X, proteoglycans, fibronectin, laminin and elastin. In addition, matrix metalloproteinase-3 can also activate other matrix metalloproteinases, such as matrix metalloproteinases 1, 7 and 9 .
  35. 35. Matrix metalloproteinase-8, also known as neutrophil collagenase or as collagenase-2, is a collagen-cleaving enzyme and the major collagenase species detected in inflamed human periodontium. .
  36. 36. Matrix metalloproteinase-13 is also termed collagenase- 3 and plays a role in the degradation of collagenous matrix. In addition to fibrillar type I, XI and III collagens, it degrades type IV, IX, X and XIV collagens, gelatin, tenascin-C, fibronectin and proteoglycan core proteins
  37. 37.  In cultured porcine periodontal ligament cells, expression of matrix metalloproteinase-13 was enhanced by tumor necrosis factor-alpha, transforming growth factorbeta1 and by keratinocyte growth factor in the presence of heparin. Expression of matrix metalloproteinase- 13 was induced in non differentiated epithelial cells during chronic inflammation as a result of exposure to cytokines and collagen .
  38. 38. Matrix metalloproteinase-24 (also known as membrane type1-matrix metalloproteinase) is a membrane- anchored type-1 matrix metalloproteinase. Although not classified as a member of the collagenases group, it has been demonstrated that this matrix metalloproteinase plays a physiologically relevant role in type-I collagen remodeling (87).
  39. 39. In summary, the expression of different matrix metalloproteinases in normal and diseased human gingiva might contribute to periodontal physiological and pathological processes.
  40. 40. Influence of viral infections on epithelial barrier function
  41. 41. These data suggest that HIV-associated tight junction disruption of the mucosal epithelia may potentiate human papillomavirus infection and subsequent development of human papillomavirus-associated neoplasia.
  42. 42. Human papilloma viruses infect mucosal and cutaneous epithelia and induce lesions that can persist and progress to cancer; this is particularly so for human papillomaviruses 16 and 18. The human papillomavirus- 16 genome encodes three transforming proteins: E5, E6 and E7 .
  43. 43. Progression of most solid tumors is characterized by an increase in secretion and activation of matrix metalloproteinases produced by either the tumor cells or tumor-associated fibroblasts.
  44. 44. Using three-dimensional organotypic raft cultures, Barbaresi et al. (17) showed that HaCaT human keratinocytes, expressing human papillomavirus- 16 E5, formed a perturbed epithelium with defective differentiation, invasion into the collagen matrix, progression through the cell cycle and production of matrix metalloproteases, especially of matrix metalloprotease-9.
  45. 45. Epstein–Barr virus is a human herpesvirus that infects both lymphoid and epithelial cells and contributes to the pathogenesis of several lymphomas and carcinomas. Using a lytic transactivator of Epstein– Barr virus induction of matrix metalloprotease-3 expression, migration and invasion of Epstein–Barr virus-infected cells has been demonstrated .
  46. 46. Chronic or dysregulated inflammation has long been appreciated as contributing to tumor development, in part through modulation of the tumor microenvironment . Both P. gingivalis and F. nucleatum establish chronic infections that involve intracellular persistence within epithelial cells, can spread systemically and cause extra-oral infections, and have well- characterized immune disruptive properties.
  47. 47. F. nucleatum is strongly proinflammatory, and McCoy et al. [7] demonstrated a positive correlation between mRNA levels for several local cytokines and Fusobacterium species in CRC cases.  Furthermore, in the ApcMin/+ mouse model of intestinal tumorigenesis, F. nucleatum recruits tumor-infiltrating immune cells, thus generating a proinflammatory microenvironment that is conducive for CRC progression.
  48. 48. Remarkably, P. gingivalis possesses multiple mechanisms for inhibition of apoptosis in epithelial cells. Expression of microRNAs (miRs) is modulated, and up- regulation of miR-203 leads to inhibition of the negative regulator SOCS3 and subsequent suppression of apoptosis.
  49. 49.  F. nucleatum also activates p38, leading to the secretion of MMP-9 and MMP-13 (collagenase 3). Similar to MMP-9, MMP-13 plays an important role in tumor invasion and metastasis. Recently, a more direct relationship between F. nucleatum and CRC was demonstrated whereby the fusobacterial adhesin FadA binds to E-cadherin on colon cancer cells and activates b-catenin signaling .
  50. 50. Oral infections and systemic diseases
  51. 51. Cardiovascular disease and periodontitis  It is well known that bacteremia occurs after extraction, scaling, and probing . Also, less invasive procedures such as removal of sutures and conservatory dentistry procedures such as drilling and placement of rubber dam, matrix band, and wedges may cause bacteremia . Bacteremia after mastication and oral hygiene procedures is not uncommon.
  52. 52. Compared with bacteremia caused by treatment in the dental office, multiple daily bacteremias implies a large microbial burden on the organism due to a cumulative effect and may be the most serious factor in the development of chronic disease. Periodontal inflammation facilitates the entrance of bacteria into the bloodstream .
  53. 53. The significance of bacteremia with oral bacteria may depend on the type of bacteria transferred to the bloodstream. Porphyromonas gingivalis, considered an important pathogen in the development of periodontitis, may induce thrombus formation by aggregating platelets [36]. Because traces of Porphyromonas gingivalis have been revealed in coronary and carotid atheromas , such a pathway may be important.
  54. 54. Platelets also may interact with supragingival plaque bacteria because they appear to selectively bind strains of Streptococcus sanguis, which result in thrombus formation .
  55. 55. An indirect pathogenic role of periodontal bacteria may be due to the influx of inflammatory cells into large blood vessels in association with bacteremia and lipopolysaccharide produced by gram-negative bacteria.
  56. 56. The resulting production of cytokines such as interleukin (IL)-1b and tumor necrosis factor (TNF), prostaglandins, and growth factors including platelet-derived growth factor, fibroblast growth factor, and granulocyte macrophage colony-stimulating factor may contribute to thickening of the arterial wall because several of these substances are atherogenic .
  57. 57. Another pathway may be that the inflammatory response associated with periodontitis elevates the levels of acute-phase proteins including fibrinogen and C-reactive protein in the general circulation . Because fibrinogen and C-reactive protein are risk factors for CVD , this also may explain a link between CVD and periodontitis.
  58. 58. Possible biological mechanisms linking periodontal and cardiovascular disease include molecular mimicry between the bacterial heatshock protein GroEL and human heat-shock protein 60 (hHSP60). This hypothesis, first suggested by Wick et al., involves crossreactivity between the immune response mounted against a bacterial infection and hHSP60 expressed on stressed or damaged endothelial cells.
  59. 59. Yamazaki et al. [41] have shown that T-cells reactive with both GroEL and hHSP60 have identical nucleotide sequences in their T- cell receptor b-chain genes, and that such T-cells exist both in the atherosclerotic plaques themselves and in the periodontal tissues.
  60. 60. Metastatic inflammation. Soluble antigen may enter the bloodstream, react with circulating specific antibody, and form a macromolecular complex. These immunocomplexes may give rise to a variety of acute and chronic inflammatory reactions at the sites of deposition.
  61. 61. Periodontal pathogens may summon polymorph nuclear leukocytes and monocytes. This process may generate oxidative stress as well as periodontal tissue destruction.  Reactive oxygen intermediates produced by this stress may oxidize low-density lipoprotein cholesterol, which is a risk factor for CVD.
  62. 62. Concurrently, the by-products of these leukocytes may stimulate the liver to express CRP, IL-6, fibrinogen, and other proinflammatory mediators. These molecules in turn initiate the inflammatory process leading to atheroma formation in the endothelium.
  63. 63. Diabetes mellitus and periodontitis Patients with DM of long duration appear to be characterized by more frequent and more advanced loss of attachment, and the periodontal health may deteriorate more rapidly in poorly controlled diabetics than in control patients without DM .
  64. 64. Impaired function of neutrophils, including reduced chemotaxis , adherence , and phagocytosis, may be the most significant factor leading to increased susceptibility to periodontal disease.
  65. 65. Pneumonia and oral bacteria Respiratory pathogens may also be harbored in subgingival bacterial samples. Isolates from deep periodontal pockets have demonstrated the presence of Enterobacteriaceae , and other researchers have isolated the same organisms in 8% and Staphylococcus aureus from 46% of periodontitis patients .
  66. 66. In addition to these findings, it has been reported that the offending organisms in suppurating respiratory anaerobic infections with considerable mortality most often originate from the subgingival environment .
  67. 67. Rheumatoid arthritis and periodontitis Periodontitis and rheumatoid arthritis share several characteristics. They are both clinically characterized by local destruction of hard and soft tissue as a consequence of an inflammatory response. During the inflammatory response, local cells are stimulated to release cytokines and matrix metalloproteinases, factors that are essential in the pathogenesis of both diseases.
  68. 68. An altered function of the inflammatory response and the metabolism of soft and hard tissues (caused, for example, by genetic polymorphisms that possibly alter the cytokine and matrix metalloproteinase expression) may turn out to be identical pathogenic factors.
  69. 69. Preterm birth and low birth weight Because prostaglandins stimulate the myometrium in the uterus, the amount of the prostaglandins PGE2 and PGE2a in chorion is decisive for the onset of labor. The syntheses of prostaglandins increase under the influence of the cytokines IL-1, IL-6, and TNF.
  70. 70. Periodontitis causes bacteremia, with gram-negative bacteria releasing lipopolysaccharides, and this bacterial product initiates the production of cytokines by inflammatory cells. These cytokines may stimulate the production of prostaglandins in chorion, resulting in labor .
  71. 71. oral infection be a risk factor for Alzheimer's disease
  72. 72. Alzheimer’s disease (AD) is a scourge of longevity that will drain enormous resources from public health budgets in the future. Currently, there is no diagnostic biomarker and/or treatment for this most common form of dementia in humans. AD can be of early familial-onset or sporadic with a late-onset.
  73. 73. Apart from the two main hallmarks, amyloid-beta and neurofibrillary tangles, inflammation is a characteristic feature of AD neuropathology. Inflammation may be caused by a local central nervous system insult and/or by peripheral infections.
  74. 74. Numerous microorganisms are suspected in AD brains ranging from bacteria (mainly oral and non-oral Treponema species), viruses (herpes simplex type I), and yeasts (Candida species). A causal relationship between periodontal pathogens and non-oral Treponema species of bacteria has been proposed via the amyloid- beta and inflammatory links.
  75. 75. Periodontitis constitutes a peripheral oral infection that can provide the brain with intact bacteria and virulence factors and inflammatory mediators due to daily, transient bacteremias. If and when genetic risk factors meet environmental risk factors in the brain, disease is expressed, in which neurocognition may be impacted, leading to the development of dementia.
  76. 76. The most likely pathway for dissemination of oral microorganisms to the brain is through the blood stream. Dental treatment as well as brushing, flossing, chewing, and use of tooth picks in a patient with periodontitis will release a bacteremia. This can occur several times during the day and has been estimated to last for up to 3 hours for oral bacteria.
  77. 77. The bacteremia is usually contained by immune cells of the body. However, in people with reduced immune defense, e.g. older individuals, bacteria may localize to crevices of the oral cavity and vascular channels.
  78. 78. An intact BBB prevents microorganisms in the blood from accessing the brain. However, aging favors overgrowth of oral microorganisms, particularly anaerobic bacteria and facultative yeasts that established earlier in life and provoked pro-inflammatory responses that weakened the BBB .
  79. 79. Notably, magnetic resonance imaging (MRI) confirmed loss of BBB integrity in a mouse model of disseminated candidosis .  Loss of integrity allows microorganisms to spread through the blood stream and quietly contribute in the pathogenesis of AD.
  80. 80. Nanoparticles and the control of oral infections
  81. 81. The potential of antimicrobial nanoparticles to control oral infections is reviewed. Such particles can be classified as having a size no greater than 100 nm and are produced using traditional or more novel techniques..
  82. 82. Exploitation of the toxic properties of nanoparticles to bacteria, fungi and viruses, in particular metals and metal oxides, as well as their incorporation into polymeric materials have increased markedly over the past decade. The potential of nanoparticles to control the formation of biofilms within the oral cavity, as a function of their biocidal, anti- adhesive and delivery capabilities, is now receiving close attention
  83. 83. For example, the antimicrobial effectiveness of metallic nanoparticles has been suggested to be due both to their size and high surface-to-volume ratio. In theory, these characteristics should allow them to interact closely with microbial membranes and thus elicit an antimicrobial effect that is not solely due to the release of metal ions.
  84. 84. Photodynamic therapy and the use of nanoparticles to control oral biofilms
  85. 85. Biofilms Photodynamic therapy is very well suited for the control of bacteria in oral plaque biofilms where there is relatively easy access for application of the photosensitising agent and light sources toareas requiring treatment .
  86. 86. Killing of micro-organisms with light depends upon cytotoxic singlet oxygen and free radical generation by excitation of a photoactivatable agent or sensitiser. The result of excitation is that the sensitiser moves from an electronic ground state to a triplet state, which then interacts with microbial components to generate cytotoxic species.
  87. 87. One of the advantages of light-activated killing is that resistance to the action of singlet oxygen is unlikely to become widespread in comparison with that experienced with more traditional chemical antimicrobial agents. The most commonly tested sensitisers on bacteria havebeen tricyclic dyes (e.g. methylene blue, erythrosine), tetrapyrroles(e.g. porphyrins) and furocoumarins (e.g. psoralen). Use of nanopar-ticles within this area is now receiving attention.
  88. 88. The safe use of nanotechnology and the design of nanomaterials for biological applications involve a thorough understanding of the interface between these materials and biological systems. The interface comprises three interacting components: (i) the surface of the nanoparticle; (ii) the solid–liquid interface and the effects of the surrounding medium; and (iii) the contact zone with biological substrates.
  89. 89. The nanoparticle characteristics of most importance with regard to interaction with biological systems, whether mammalian or microbial, are chemical composition, surface function, shape and number of sides, porosity and surface crystallinity, size heterogene- ity, roughness, and hydrophobicity or hydrophilicity.
  90. 90. Anti-adherent and antifungal effects were shown using buccal epithelial cells treated with non-drug-loaded poly(ethylcyanoacrylate) nanoparticles. Nanoparticles were prepared using emulsion polymerisation and were stabilized with cationic, anionic or non-ionic surfactants. Cationic surfactants, e.g. cetrimide, whichare known antimicrobial agents, were the most effective inreducing C. albicans blastospore adhesion and demonstrated agrowth-inhibitory and biocidal effect against the yeast.
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