Chronic periodontitis afflicts the majority of human adults and is the most important cause of tooth loss. Evidence now being acquired demonstrates that periodontal destruction is cyclic and that active destruction is accompanied by the acute inflammatory process. Polymorphonuclear leukocytes (PMNs) seem to be especially important both in host defense and tissue destruction. Humans and animals having defects in PMN function manifest early-onset severe periodontitis. Products of arachidonic acid metabolism are present in inflamed periodontal tissues and there is strong evidence that they are mediators of several destructive processes. Leukotriene B4 (LTB4) is a potent chemotactic and chemokinetic agent and induces PMN adhesion, extravasation, and degranulation. A synergistic effect between the leukotrienes and the prostaglandin, PGE2 is most likely important in the host's inflammatory response. The goals of this application are to understand the role arachidonic acid metabolites play in the pathogenesis of periodontal disease and investigate the potential use of chemotherapeutic agents which modify these metabolites. Arachidonic acid metabolism in PMNs from individuals with early onset periodontitis will be compared to normal PMNs. Release levels of arachidonic acid metabolites (PGE2, TXB2 and LTB4), the effect of pathway inhibition, and the effect of leukotrienes on chemotaxis, enzyme degranulation, cAMP levels, and superoxide generation will be tested. The effect of substances known to be present in diseased tissue on arachidonic acid metabolism will be evaluated. Using an in vivo animal model of acute periodontitis, the concentrations and temporal sequence of PGE2, TXB2 and LTB4 will be determined using radioimmunoassay. Several inhibitors of selective metabolic pathways of arachidonic acid will be tested using the same animal model. By understanding the relative roles of the prostaglandins and leukotrienes on cellular basis, the development of a chemotherapeutic adjunct to periodontal therapy can be derived. Successful completion of the proposed research may be expected to result in improved and simplified ways to treat and control the periodontal diseases.
