OXIDANTS AND CADMIUM-INDUCED MICROVASCULAR INJURY

氧化剂和镉引起的微血管损伤

• 批准号: 2592209
• 负责人: JOHN G WOOD
• 金额: $ 7.5万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2592209
• 关键词: antioxidants; blood toxicology; cadmium; cardiovascular disorder epidemiology; cell adhesion; diabetes mellitus; endothelin; environmental contamination; gene expression; gene targeting; genetically modified animals; hemorrhagic shock; intravital microscopy; laboratory mouse; leukocytes; liver; metallothionein; muscle; nitric oxide; oxidative stress; toxicology; vascular endothelium; vascular endothelium permeability

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.

描述 最近的体外研究表明镉的毒性作用 内皮细胞可能涉及反应性氧化剂的产生。 此外， 镉迅速诱导这些细胞中金属硫蛋白的表达， 可以通过抗氧化作用防止镉引起的损伤。 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的关键事件 损伤和随后的器官损伤。 该提案的具体目标是 1）使用活体显微镜确定大小和 镉暴露后微血管损伤的时间过程（有证据表明 通过白细胞粘附，增加静脉对血浆蛋白的通透性，以及 增加小静脉内皮细胞对激光诱导损伤的敏感性）； 2）评估活性氧化剂在镉诱导的微血管中的作用 功能障碍（通过抗氧化剂的减弱和在 MT 转基因小鼠，MT 敲除小鼠的增强，内皮细胞增加 金属硫蛋白，以及一氧化氮、内皮素-I 和血浆的增加 TBAR）； 3) 确定慢性过程中是否产生活性氧化剂 镉暴露会加剧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微血管变化 提睾肌和肝脏。 中心目标是评估 微循环障碍发展过程中氧化剂的产生 接触镉后会加剧心血管疾病。