Neutrophils and Periodontitis in Diabetes

糖尿病现在在美国已经达到流行病的状态，影响了6.5%的普通人口，并继续以非常惊人的速度增长。牙周病被称为糖尿病的第六大并发症。糖尿病和牙周病之间有一种相互关系，每一种情况都会加剧另一种情况。我们最近观察到，来自糖尿病患者的中性粒细胞和单核细胞含有升高的二酰基甘油酯（DAG），增强的蛋白激酶C （PKC）活性，并且可以比健康人的细胞释放更多的超氧化物和/或肿瘤坏死因子- α。超氧化物、细胞因子和基质金属蛋白酶在糖尿病牙周组织的破坏中起重要作用。重要的是，在兔模型中发现，某些内源性抗炎脂质（由花生四烯酸和二十碳五烯酸的跨细胞代谢产生）在抑制糖尿病中性粒细胞的超氧化物释放和阻断牙周病方面非常有效。

DESCRIPTION: Diabetes has now reached epidemic status in the United States, affects 6.5% of the general population, and continues to increase at a very alarming rate. Periodontal disease is referred to as the sixth complication of diabetes. There is a reciprocal relationship between diabetes and periodontal disease where each condition exacerbates the other. We have recently observed that neutrophils and monocytes from diabetic patients contain elevated diacylglycerides (DAG), enhanced activity of protein kinase C (PKC), and can release significantly more superoxide and/or tumor necrosis factor-alpha than cells from healthy individuals. Superoxide, cytokines and matrix metalloproteinases play a significant role in the destruction of periodontal tissues in diabetes. Importantly, certain endogenous, anti-inflammatory lipids that result from transcellular metabolism of arachidonic and eicosapentaenoic acid (lipoxins, resolvins) were found to be highly effective in inhibiting superoxide release from diabetic neutrophils and blocking periodontal disease in a rabbit model. In this proposal, we will: 1) determine the molecular mechanisms responsible for alterations in DAG and PKC in diabetic patients; 2) uncover the biochemical basis for priming of neutrophils/monocytes in diabetes, and determine if this priming is prevented when patients are brought under glycemic control and/or treated for periodontal disease; 3) determine the signal transduction pathways by which advanced glycation end products (AGE) prime neutrophils; and 4) determine if certain endogenous anti-inflammatory lipid mediators (e.g., lipoxins, resolvins) can limit the inflammatory response in diabetes by blocking the enhanced functional responses of neutrophils and monocytes from these patients. Techniques of modern biochemistry, immunology and cell biology will be employed in these investigations. These studies have the potential of leading to better methods of treating periodontal disease and perhaps other complications of diabetes.