ENVIRONMENTAL REGULATION OF NEUTROPHIL EXTRAVASATION

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The migration of neutrophils from the peripheral vasculature to the periodontal tissues is an essential component of the host's protective response to the accumulation of microbial plaque. Neutrophil extravasation to infected sites is mediated by the local release of inflammatory molecules, expression of adhesion molecules by endothelial and neutrophil cell populations, and the stimulated migration of neutrophils in response to the release of chemotactic proteins and lipids. Since altered neutrophil function has been implicated in the pathogenesis of periodontal disease, the overall. objectives of this proposal are to develop an in vitro model for studying the influence of environmental factors on neutrophil extravasation at sites of. periodontal inflammation and to characterize any deleterious sequelae that occur. These objectives will be addressed by the following specific aims: (1) To establish an in vitro tissue culture construct of the human blood vessel wall using a dual chamber system, that will allow the study of the adherence and physiologic migration of neutrophils through endothelium, basement membrane and type I collagen in response to chemotactic proteins and lipids. (2) To study the modulation of adhesiOn molecule expression by neutrophils and endothelium in response to chemotactic stimulation in the presence of TNF- a, IL-1, LPS, Porphyromonas gingivalis or Actinobacillus actinomycetemcomitans; analysis will use in situ labeling of the blood vessel wall construct and FACS analysis of single cell suspensions. (3) To characterize the effects of altered adhesion molecule expression on transendothelial migration of neutrophils and the pathologic changes in endothelial cells that occur as a result of the altered neutrophil- endothelial cell interaction. These studies will provide important information on the environmental effects of specific inflammatory molecules on the interaction of neutrophils and endothelial cells. In addition, the development of this in vitro construct will provide an excellent model for future studies of the effects of host and bacterial inflammatory,molecules on leukocyte extravasation in the periodontal diseases.