ELEVATED GLUCOSE EFFECTS ON CYTOKINE MEDIATED ENDOTHELIAL LEUKOCYTE/INTERACTION

糖尿病患者的感染比糖尿病患者更常见和严重。 在一般人群中。这些人对感染的易感性 患者与中性粒细胞功能障碍有关，最近 白细胞与内皮细胞相互作用受损白细胞附着 是有效的炎症或免疫治疗的早期和决定性事件。 反应白细胞-内皮细胞相互作用通过来自 血源性活化剂，即细胞因子。 hyperplasia是一个最 导致糖尿病慢性并发症的重要危险因素 糖尿病。 虽然建议，高血糖症的贡献， 糖尿病患者白细胞-内皮细胞相互作用受损， 已最终确立。 因为磷酸肌醇的改变 代谢是其中一种被提出的分子机制， 血糖升高发挥其病理作用，似乎有必要探讨 这个转换过程更加紧密。本项目旨在研究 葡萄糖水平升高对甜菜碱诱导的信号传导的影响， 允许内皮细胞-白细胞相互作用， 炎症反应。微血管来源的细胞培养物（即牛 视网膜）作为实验模型。细胞因子诱导信号 在内皮细胞中，将通过测定 3H-花生四烯酸标记培养物中甘油二酯的产生 细胞.从3H-磷酸肌醇生产的测定 FURA-AM中肌醇标记细胞和细胞内Ca~（2+）动员 加载细胞。信号转导将与内皮细胞-白细胞 通过细胞粘附分子的表达检测相互作用， 白细胞粘附试验。这项研究将扩大我们对 高血糖通过生化机制改变 靶组织如血管内皮的生理反应， 特别是它对糖尿病易感性增加的贡献， 患者感染。 所取得的成果最终可能导致 旨在预防慢性疾病出现的治疗措施 糖尿病患者的并发症。

Infections in diabetes mellitus patients are more common and severe than in the general population. The susceptibility to infections in these patients has been associated with neutrophil dysfunction and more recently to an impaired leukocyte-endothelial interaction. Adhesion of leukocytes is an early and determinant event for an effective inflammatory or immune response. Leukocyte-endothelial interaction is enhanced by signals from blood borne activators, i.e. cytokines. Hyperglycemia is one of the most important risk factors leading to chronic complications in diabetes mellitus. Although suggested, the contribution of hyperglycemia to an impaired leukocyte-endothelial interaction in diabetic patients, has not been conclusively established. Since alterations in phosphoinositide metabolism is one of the proposed molecular mechanisms through which elevated glucose exerts its pathologic effect it seems relevant to explore this transduction process more closely. This project aims to study the effect of elevated glucose levels on the cytokine-induced signaling that permits the endothelial-leukocyte interaction necessary for the inflammatory response. A microvascular derived cell culture (i.e. bovine retina) will be used as the experimental model. Cytokine-induced signaling in endothelial cells will be followed through the determination of the generation of diacylglycerol in 3H-arachidonic acid labeled cultured cells; determination of production of inositol phosphates from 3H- myoinositol labeled cells and intracellular Ca2+ mobilization in FURA-AM loaded cells. Signaling will be correlated with endothelial-leukocyte interaction detected through the expression of cell adhesion molecules and leukocyte adherence tests. This study will expand our understanding of the biochemical mechanisms through which hyperglycemia alters the physiological response of target tissues such as the vascular endothelium, in particular its contribution to the increased susceptibility of diabetic patients to infections. The results obtained may eventually lead to therapeutic measures intended to prevent the appearance of chronic complications in diabetes mellitus patients.