The neutrophil plays a key role in host defense against infection due to extracellular bacteria. Considerable evidence also indicates that the neutrophil is a critical element of host defense against periodontal injury initiated by bacteria in dental plaque. In order to provide such defense, adequate numbers of neutrophils must first penetrate vascular endothelium through an adhesion-dependent process. Following extra- vasation, neutrophils must migrate toward, ingest and ultimately destroy the target bacteria. Defects in neutrophil production or function often result in increased susceptibility to recurrent bacterial infection, and appear to predispose to early-onset, severe forms of periodontal disease which may arise prior to or during puberty. Susceptibility to severe periodontitis varies widely in the adult population. Cross-sectional studies conducted at the Clinical Research Center have identified certain variables associated with increased risk of severe periodontitis. Included in this group of """"""""risk indicators"""""""" are diabetes and smoking. A key objective of studies proposed in this Clinical Research Center application is to conduct longitudinal studies necessary to establish if diabetes and/or smoking constitute true """"""""risk factors"""""""" for development of severe periodontitis. Diabetes has long been associated with increased susceptibility to infection, attributable in part to altered neutrophil function. Neutrophil adherence, chemotaxis, phagocytosis and killing are often decreased in diabetes. Vascular changes observed in diabetes may also impede neutrophil extravasation into infected tissues. Various components of tobacco smoke have also been reported to inhibit neutrophil function. The objective of this pilot study is to determine whether apparent increases in susceptibility to periodontitis seen in diabetics or smokers are associated with impaired neutrophil function. Specific parameters to be evaluated will include a) in situ crevicular leukocyte responses to casein, b) expression of cell adhesion molecules (Mac-1/CR3, L- selectin) using anti-adhesion monoclonal antibodies in conjunction with flow cytometric techniques, c) in vitro aerobic and anaerobic bactericidal activity toward Actinobacillus actinomycetemcomitans, d) neutrophil degranulation, as determined by flow cytometric analysis of right angle light scatter, and e) chemotaxin (IL-8, fMLP)-induced signal transduction (IP3 production). Neutrophil responses will be compared in a) diabetic vs. non-diabetic periodontitis patients (balanced for smoking, microflora and age), b) smoker vs. non-smoker periodontitis patients (non-diabetic only balanced for microflora and age), and c) periodontitis subjects vs. periodontally healthy (diabetic and non- diabetic, as well as smoker and non-smoker) controls. These pilot studies are designed to provide the basis for an in-depth assessment of mechanisms by which smoking and/or diabetes impairs neutrophil-mediated defenses.
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