Diabetes increases the susceptibility to infectious diseases, including periodontal disease. Periodontal disease is initiated by bacteria, but components of the host immune response are thought to contribute significantly to periodontal tissue damage. Of particular interest, free radicals such as superoxide play a prominent role both in diabetic complications and in periodontal tissue damage. Free radicals are produced in large quantities by polymorphonuclear (PMN) leukocytes, and abnormal PMN function is detected both in diabetes and in periodontal disease. This proposal is intended to help elucidate the molecular mechanisms that link diabetes and periodontal disease. The chief hypothesis to be tested is that elevated blood glucose activates PMN leukocytes, which in turn release excess superoxide causing tissue damage in the periodontium and in other tissues. A second focal point of these experiments is the evaluation of novel endogenous anti-inflammatory lipids, such as lipoxins, resolvins and docosatrienes. These molecules are formed locally during inflammation, and they antagonize the effect of PMN leukocytes and promote resolution of inflammation. Experiments are designed to test the effectiveness of stable analogs of lipoxins, defensins and docosatrienes in decreasing inflammatory tissue damage in diabetes and periodontal disease. These experiments employ a novel animal model of insulin-dependent diabetes, the Akita mice, and another mouse line, the Ncfl mice, whose PMN are deficient in superoxide generation. Akita and Ncf1 mice will be crossed to generate a double mutant experimental model in which the contribution of superoxide to diabetic tissue damage can be analyzed in alveolar bone and in soft tissue. The findings from these experiments might be important not only from the view of periodontal health, but also for diabetes research. Moreover, findings on novel lipid inhibitors of inflammation will be important in evaluating the therapeutic potential of these compounds in resolving inflammation in periodontal and other inflammations.
