LEUKOCYTE ADHESION IN COPPER DEFICIENT MICROCIRCULATION

微血管对炎症刺激的反应的调节高度依赖于 中性粒细胞与内皮细胞之间的相互作用。我们已经展示了饮食的重要作用 铜在炎症过程中与内皮细胞的各种相互作用，包括一氧化氮 (NO)介导的血管扩张、大分子渗漏和血栓形成。最近，我们研究了 日粮铜在微血管控制机制中的作用，重点是白细胞/内皮细胞 粘附力。我们已经证明，饮食中的铜限制会导致组织特异性的变化 中性粒细胞/内皮细胞的黏附和迁移。中性粒细胞堆积，表达 黏附分子ICAM-1和转录因子NF-kB在小鼠肺组织中的表达均较强 铜缺乏的大鼠与铜充足的对照组相比。根据这些结果，我们假设 膳食铜缺乏对白细胞和肺血管内皮细胞的启动作用 使肺部对炎性刺激变得高度敏感，更容易受到 发生急性肺损伤。因此，本研究的具体目的是：1)确定 日粮铜在肺微循环中与白细胞/内皮细胞的相互作用；2)确定 铜缺乏引发细胞急性炎症的机制和3)决定什么 饲料中铜的浓度在动物体内的炎症机制增强 微循环。目的1将使用肺微循环的体内和体外模型来研究 白细胞/内皮细胞的黏附和趋化。目标2将研究铜在核因子-kB中的作用 信号通路和中性粒细胞启动。目标3将在以下条件下检查这些机制 铜-边际饮食。这些实验具有特别的相关性，因为对典型的西方 饮食建议，这些饮食中的1/3到1/2提供的铜可能低于900毫克/天的RDA。

Regulation of the microvascular response to inflammatory stimuli is highly dependent upon the interactions between neutrophils and the endothelium. We have shown a significant role for dietary copper in various endothelial interactions in the inflammatory process, including nitric oxide (NO)-mediated vasodilation, macromolecular leakage, and thrombosis. Recently, we have studied the role of dietary copper in microvascular control mechanisms with an emphasis on leukocyte/endothelial adhesion. We have demonstrated that dietary copper restriction causes tissue-specific changes in neutrophil/endothelial adhesion and transmigration. Neutrophil accumulation, the expression of the adhesion molecule ICAM-1 and the transcription factor NF-kB are all greater in the lungs of copper-deficient rats compared to copper-adequate controls. Based on these results, we hypothesize that dietary copper deficiency has a priming effect on leukocytes and pulmonary vascular endothelial ceils such that the lung becomes hypersensitive to inflammatory stimuli and more susceptible to the development of acute lung injury. Therefore the specific aims of this study are to: 1) determine the role of dietary copper in leukocyte/endothelial cell interactions in the lung microcirculation; 2) determine the mechanisms by which copper deficiency primes cells for acute inflammation and 3) determine at what concentration of dietary copper the inflammatory mechanisms become enhanced in the in vivo animal microcirculation. Aim #1 will use both in vivo and in vitro models of the lung microcirculation to study leukocyte/endothelial cell adhesion and chemotaxis. Aim #2 will study the role of copper in the NF-kB signaling pathway and in neutrophil priming. Aim #3 will examine these mechanisms under conditions of copper-marginal diets. These experiments have particular relevance since analysis of typical Western diets suggest that 1/3 to 1/2 of those diets may provide less than the RDA of 900mg Cu/day.