SUPERFUND CHEMICALS AND ENDOTHELIAL CELL DYSFUNCTION

多卤代芳烃（如多氯联苯）和多环芳烃 芳烃（例如，英国石油公司（BP）被卷入了 动脉粥样硬化疾病过程。 尽管这些机制 这些环境污染物的致动脉粥样硬化潜力不是 已知的细胞功能障碍的关键事件可能发生在 内皮细胞水平。 血管内皮“交流” 与血液传播的细胞和远腔组织，并作为一个屏障， 等离子体成分的移动（例如，富含胆 脂蛋白）从血液到动脉壁。 细胞损伤或任何 破坏内皮完整性的事件， 渗透性，可能参与早期事件导致 动脉粥样硬化病变的形成。 我们认为芳香族 碳氢化合物通过引起细胞功能障碍而致动脉粥样硬化， 随后破坏内皮屏障功能。 我们 假设这些事件是由1）脂质改变 特征和脂质代谢，2）细胞色素P-450 1A 1诱导，3） 增加的氧化应激，4）DNA加合物形成和氧化应激 DNA损伤; 5）钙代谢改变。 因此 致动脉粥样硬化的脂蛋白残余物穿过 并进入动脉壁可能直接与 内皮细胞屏障功能破坏。 我们还假设， 饮食衍生的脂肪，即，碳长度不同的脂肪酸， 不饱和度，可以极大地改变细胞脂质， 氧化剂/抗氧化剂环境，从而影响芳香族 碳氢化合物介导的细胞功能障碍。 此外，这项研究 将探索某些营养物质或化学物质 具有抗氧化剂或膜稳定特性，可以保护 防止芳香烃引起的细胞损伤。 猪- 人源性内皮细胞将被培养并用于 提议的研究。 首先，我们会进行一系列的研究， 确定芳香烃介导的内皮细胞 细胞功能障碍 在第二阶段， 某些脂类和芳香烃对内皮细胞 代谢将被探索。 在第三阶段， 将进行研究以确定 在培养中选择的营养干预可以保护激动剂细胞 在上述条件下的伤害。 拟议预算的结果 研究应确定超级基金化学介导的机制 内皮细胞功能障碍及其在动脉粥样硬化中意义

Polyhalogenated aromatic hydrocarbons (e.g. PCBs) and polycyclic aromatic hydrocarbons (e.g., BP) have been implicated in the atherosclerotic disease process. Even though mechanisms of the atherogenic potential of these environmental contaminants are not known, critical events of cell dysfunction may occur at the endothelial cell level. The vascular endothelium 'communicates' with blood-borne cells and abluminal tissues and acts as a barrier to the movement of plasma components (e.g., cholesterol-rich lipoproteins) from the blood to the arterial wall. Cell injury, or any event which disrupts endothelial integrity and thus endothelia permeability properties, may be involved in the early events leading to atherosclerotic lesion formation. We propose that aromatic hydrocarbons are atherogenic by causing cell dysfunction and a subsequent disruption of endothelial barrier function. We hypothesize that these events are mediated by 1) alteration in lipid profile and lipid metabolism, 2) cytochrome P-450 1A1 induction, 3) increased oxidative stress, 4) DNA adduct formation and oxidative DNA damage, and 5) alteration of calcium metabolism. Thus, the extent of the movement of atherogenic lipoprotein remnants across and into the arterial wall may be directly correlated to the severity of endothelial cell barrier function disruption. We also hypothesize that diet-derived fats, i.e., fatty acids differing in carbon length and degree of unsaturation, can greatly alter the cellular lipid and oxidant/antioxidant environment and thus influence the aromatic hydrocarbon-mediated cell dysfunction. Furthermore, this research will explore mechanisms by which certain nutrients or chemicals having antioxidant or membrane stabilizing properties, may protect the endothelium from aromatic hydrocarbon-induced cell injury. Porcine- and human-derived endothelial cells will be cultured and used in the proposed research. First, a series of studies will be conducted to determine mechanisms of aromatic hydrocarbon-mediated endothelial cell dysfunction. In the second phase, the interactive events of certain lipids and aromatic hydrocarbons on endothelial cell metabolism will be explored. During the third phase, a series of studies will be undertaken to determine the mechanisms by which selected nutritional interventions in culture may protect agonist cell injury under the conditions cited above. Results of the proposed studies should identify mechanisms of Superfund Chemical-mediated endothelial cell dysfunction and their implication in atherosclerosis.