Thesis (M.D.S.)--University of Hong Kong, 2000. / Includes bibliographical references (leaves 83-102).

Thesis (doctoral)--Universität Tübingen, 1933.

Thesis (M.S.)--University of Louisville, 1998. / Includes bibliographical references.

Thesis (M.D.S.)--University of Hong Kong, 2004. / Also available in print.

This paper studies the correlation between three widely common chronic diseases, periodontal disease, diabetes, and obesity. The three diseases share one key factor; they not only affect human's health but also the style and quality of life. This paper evaluated the current literature regarding periodontal disease, diabetes, obesity, and their triangular relationship. The studies showed that the three chronic diseases are related to each other in a triangular relationship. Increased adiposity manifested by BMI greater than 30, leads to increased systemic inflammation through the release of inflammatory adipokines from the fatty deposits, this leads to the development of diabetes mellitus by different mechanisms, partly by destruction of the islet cells of Langerhans and partly by insulin resistance. One of the complications of diabetes mellitus is periodontal disease, which is a list of clinical conditions that adversely affect the health of the periodontium. Moreover, current literature provides evidence that the relationship between diabetes and periodontal disease is bidirectional. Evidence from current studies is showing that periodontal disease might lead to the development of diabetes by increasing the systemic inflammation, this occurs by the invasion of periodontal pathogens of the endothelial cells where they elicit an exacerbated systemic inflammation which might lead to the development of diabetes and other chronic conditions. This paper shows the importance of collaborative work between the dental and the medical professionals to ensure the overall health of an individual. Primary care physicians are encouraged to refer patients with poor glycemic control to dentists for an assessment of the health of their oral cavity and vice versa; dentists should be more aware of the systemic complications of oral diseases and should educate their patients about such relationships.

Objectives: Periodontal disease is a chronic inflammation resulting in periodontal attachment loss. Keratinocyte Growth Factor-1 (KGF-1) is upregulated in chronic inflammation and specifically stimulates epithelial cell proliferation by signaling through the epithelial-specific Keratinocyte Growth Factor Receptor (KGFR). First, we examined KGF-1 and KGFR expression and localization in human periodontal tissues. Second, we extended these studies by developing an in vitro mechanical wound model to mimic trauma to the periodontal pocket epithelium and examined ligand independent KGFR activation and cell migration. Methods: In our study of human gingival tissues, we used immunohistochemistry and laser capture microdissection with RT-PCR to analyze KGF-1 and KGFR expression and localization. To study ligand independent KGFR phosphorylation, KGFR internalization along the wound edge was imaged using immunohistochemical staining and KGFR phosphorylation confirmed using immunoprecipitation with western blotting. Wounding induced oxidative stress was detected using DCFH-DA (2',7'-dichlorofluorescin diacetate) and modulated by pretreatment with an antioxidant. Changes in migration were examined in the presence or absence of pathway specific inhibitors. Results: KGF-1 protein localized to areas of junctional and basal oral epithelial cells was significantly increased in periodontal pocket epithelium (p<0.01) and oral epithelium (p<0.05) of disease-associated tissues. KGFR localized to the junctional and the parabasal cells of oral epithelium, and was increased in disease-associated pocket epithelium (p<0.05). Laser capture microdissection with RT-PCR confirmedKGF-1 and KGFR were specifically expressed by connective tissue and epithelium, respectively. In our cell culture model, mechanical wounding induced ligand independent KGFR activation. ROS (Reactive Oxygen Species) generation along the wound edge was associated with KGFR activation and scavenging of ROS reduced KGFR phosphorylation. The c-Src family inhibitor, PP1, significantly inhibited KGFR phosphorylation. Functionally cell migration was reduced by PP1 (82.7%), SU5402(70%) and PD98059 (57%). Conclusions: KGF-1 and KGFR proteins are expressed in health but significantly induced in human diseased periodontal tissues. Microwounding associated generation of ROS mediates KGFR phosphorylation via c-Src kinase signaling and induced wound edge cell migration. Therefore, regulation of epithelial cell behavior associated with the onset and progression of periodontal disease may possibly be mediated by two related but distinct mechanisms. (1) Ligand-dependent activation of KGFR due to upregulation of KGF-1. (2) Ligand-independent activation of KGFR due to chronic microwounding. / Dentistry, Faculty of / Graduate

Periodontal disease is a condition in which the gums and bones surrounding the teeth are inflamed. It is a common cause of oral discomfort and tooth loss, but in recent years has been linked to a variety of systemic problems. Among them is cardiovascular disease, which is the top cause of death in the developed world. There is evidence that periodontal pathogens invade the bloodstream from the gingival pockets and contribute to the progression of disease through a variety of different mechanisms. First, they initiate the systemic inflammatory process by invading and activating vascular endothelial cells to upregulate adhesion molecules and chemokines, which then in turn activate macrophages to take up low density lipoprotein and deposit it on the luminal wall. Atherosclerotic plaque is pro-thrombotic, which increases the chances of forming blood clots and ischemic attacks. Periodontal pathogens also can induce the proliferation of antibodies that can cross-react with self-antigens, resulting in an autoimmune disease. The presence of these pathogens also causes oxidative stress through the production of reactive oxygen species, which is highly damaging. Since these pathogens have many ways of contributing to cardiovascular diseases, it has been hypothesized that treating the periodontal problems will help prevent the progression of cardiovascular disease. Several studies show that addressing periodontitis has resulted in decreased levels of inflammatory markers like C-reactive protein, interleukin-6, and fibrinogen, lower incidences of stroke, decreased blood pressure and lipid levels, and a lower left ventricular mass.

Bibliography: leaves 107-138.

published_or_final_version / abstract / Dentistry / Master / Master of Dental Surgery

Doctor of Philosophy / Profound perturbation of epithelial structure is a characteristic feature of the immunopatholoical response to bacterial antigens considered to be central in the pathogenesis of the destructive lesion of periodontitis. The pathological basis for the disturbance of epithelial structure is not understood. It was demonstrated that the structural integrity and functional differentiation of the lining epithelium is compromised in relation to inflammatory changes associated with destructive periodontitis. In the pathological lining epithelium of the periodontal pocket there was a marked reduction of epithelial cadherin important in intercellular adhesion, of involucrin, a marker of terminal differentiation, and of the gap junction connexions that form intercellular communication channels. These changes were associated with alterations of filamentous actin expression, collectively indicating profound perturbation of epithelial structure. The data reported support the concept that the ability of the pathological lining epithelium to function as an effective barrier against the ingress of microbial products into the tissues is severely compromised (Ye et al., 2000). In addition, a recent study (Ye et al., 2003) by Western analysis of serum IgG from all 22 patients with chronic periodontitis tested indicated recognition of multiple epithelial components in individual patterns. In contrast, subjects with a healthy periodontium displayed only trace recognition of epithelial antigens. Levels of epithelial-reactive antibodies were significantly correlated with attachment loss as an indication of disease activity. To investigate a possible relationship between the bacterial flora adjacent to the diseased sites and the presence of epithelial-reactive antibodies, subgingival plague samples were taken from deep periodontal pockets and cultured anaerobically. Gram positive bacteria containing antigens potentially cross-reactive with epithelial cells were reproducibly isolated by probing membrane colony lifts with affinity-isolated (epitheial-specific) antibodies. The bacteria were identified as streptococci (S. mitis, S. constellatus and two S. intermedius strains) and Actinomyces (A. georgiae, and A. sp. oral clone) by 16S rDNA sequence homology. Recognition by affinity-isolated antibodies of antigens from the captured organisms was confirmed by Western analysis. Conversely, absorption of affinity-isolated antibodies with bacterial species specifically reduced subsequent recognition of epithelial antigens. To identify the auto-antigens, a human keratinocyte cDNA expression library in Lambda phage was probed using a pooled sera. Groups of responders were detected for CD24 (a recently described adhesion molecule also known as P-selectin ligand), antioxidant protein 2 (a newly recognised member of the thiol-dependment anti-oxidant proteins), lavtate dehydrogenase A, the transcription factor NFAT5, and for three genes encoding novel proteins. Six identified bacteria, especially S intermedius were demonstrated to absorb antibodies reaching with identified auto-antigens in patterns varying between individuals. This evidence indicated that during the course of periodontits, subjects develop increased levels of antibodies to common oral bacteria amongst which are included tissue cross-reactive antigens. Periodontitis could therefore present a risk for the subsequent initiation or exacerbation of a broad spectrum of disease processes including autoimmune, inflammatory, proliferative and degenerative disorders.