OXIDANTS AND CADMIUM-INDUCED MICROVASCULAR INJURY

描述 最近的体外研究表明，镉对人体的毒性作用 内皮细胞可能参与了反应性氧化剂的生成。此外, 镉可迅速诱导这些细胞中金属硫蛋白的表达，从而 可能通过抗氧化作用对镉的损伤起到保护作用。一 对这些发现的解释是，镉诱导的内皮氧化剂 生成可能是微血管发育过程中的关键事件 损伤和随后的器官损伤。这项提议的具体目的是 目的：1)利用活体显微镜，确定 镉暴露后微血管损伤的时程(已证实 通过白细胞黏附，增加小静脉对血浆蛋白的通透性，以及 静脉内皮细胞对激光损伤的敏感性增加)； 2)评价活性氧化剂在镉诱导的微血管中的作用 功能障碍(表现为抗氧化剂和 MT转基因小鼠，MT基因敲除小鼠的增强，内皮细胞增加 金属硫蛋白，一氧化氮、内皮素-I和血浆的增加 TBARs)；以及3)确定慢性阻塞性肺疾病期间反应性氧化剂的生成 镉暴露增加微血管损伤的严重程度 失血性休克、败血症或糖尿病。拟议的研究将利用 活体显微镜直接检查血管内微血管改变 提睾肌和肝脏。中心目标是评估 氧化剂的产生与微循环障碍的发生和发展 暴露于镉后，心血管疾病加重。

DESCRIPTION Recent in vitro studies have suggested that toxic effects of cadmium on endothelial cells may involve reactive oxidant generation. In addition, cadmium rapidly induces expression of metallothionein in these cells, which may protect against cadmium-induced injury through antioxidant effects. One interpretation of these findings is that cadmium-induced endothelial oxidant generation may be a critical event in the development of microvascular injury and subsequent organ damage. The specific aims of this proposal are to: 1) establish, using intravital microscopy, the magnitude and time-course of microvascular injury following cadmium exposure (as evidenced by leukocyte adhesion, increased venular permeability to plasma protein, and increased sensitivity of venular endothelial cells to laser-induced injury); 2) evaluate the role of reactive oxidants in cadmium-induced microvascular dysfunction (as evidenced by attenuation by antioxidants and in MT-transgenic mice, augmentation in MT knock-out mice, increased endothelial metallothionein, and increases in nitric oxide, endothelin-I, and plasma TBARS); and 3) determine whether reactive oxidant generation during chronic cadmium exposure augments the severity of microvascular injury during hemorrhagic shock, sepsis, or diabetes. The proposed studies will utilize intravital microscopy to directly examine microvascular alterations in the cremaster muscle and liver. The central goal is to evaluate the role of oxidant generation in the development of microcirculatory impairment and enhanced cardiovascular disease following exposure to cadmium.