PATHOGENESIS OF TOXICITY OF VANADIUM COMPOUNDS

钒化合物毒性的发病机制

• 批准号: 6106320
• 负责人: John J Godleski
• 金额: $ 26.89万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6106320
• 关键词: aerosols; alveolar macrophages; atomic absorption spectrometry; cell sorting; cellular pathology; cytokine; cytotoxicity; electron microscopy; environmental contamination; environmental toxicology; human subject; laboratory rat; leukocyte oxidative burst; pathologic process; protein tyrosine phosphatase; vanadium

Vanadium is listed as an inorganic superfund target chemical, known to have toxic health effects, and found at superfund sites. Inhalation is a frequent route of entry into the human body. The ultimate chemical species of vanadium to enter cells relates to its chemical form in environmental particles as well as the fluid media encountered in tissues. The extracellular liquids and their contents as well as intracellular compartments may influence the species of vanadium that ultimately interacts with cellular constituents to produce adverse effects. Two important adverse responses in the lung related to vanadium exposure are the generation of active oxygen metabolites and the induction of pro- inflammatory cytokines. These events occur in pulmonary alveolar macrophages (PAMS) which play a central role in the protection of the lung and the development of pulmonary disease. The specific aims of the studies that we propose are; 1) to define the dissolution patterns and chemical forms of vanadium compounds in the lung, 2) to determine the dose of vanadium compounds in intracellular compartments of PAMs and other lung cells; 3) to determine mechanisms by which these compounds produce massive increases in active oxygen metabolites; 4) to determine mechanisms by which vanadium compounds induce pro-inflammatory cytokines; and 5) to assess these mechanisms of toxicity in human PAMs obtained by bronchoalveolar lavage from workers occupationally exposed to vanadium compounds and non- smoking, non-exposed human volunteers. Assessments of these cells will focus upon the mechanisms defined in our other specific aims so that all our studies will model human exposure at a superfund site. The correlation of our research with that of Project 5 will allow us to directly correlate our mechanistic findings with an in vivo human exposure situation. We will use the Zeiss CEM902 electron microscope's electron energy loss technology for quantification and direct visual correlation of elemental localization and pathologic effects within the cytoplasm of cells. Biochemical, pharmacologic, and molecular approaches will be used to define mechanisms of toxicity/ The novel application of these sophisticated technologies in our proposed studies will offer new insights into intracellular dose- response relationships and mechanisms of toxicity of vanadium compounds.

钒被列为一种无机超级基金目标化学化学物质，已知有 有毒的健康影响，并在超级基金站点发现。 吸入为 经常进入人体的途径。 最终的化学物种 进入细胞的钒的化学形式与环境中的化学形式有关 颗粒以及在组织中遇到的流体培养基。 这 细胞外液体及其含量以及细胞内 车厢可能会影响最终 与细胞成分相互作用以产生不良反应。 二 与钒暴露有关的肺中重要的不良反应是 活性氧代谢产物的产生以及促进 炎症细胞因子。 这些事件发生在肺肺泡中 巨噬细胞（PAM）在保护肺中起着核心作用 以及肺部疾病的发展。 研究的具体目的 我们建议的是； 1）定义溶解模式和化学 肺中钒化合物的形式，2）确定剂量 PAM和其他肺部细胞内室中的钒化合物 细胞； 3）确定这些化合物产生大量的机制 活性氧代谢产物的增加； 4）确定机制 钒化合物诱导促炎性细胞因子； 5）评估 这些通过支气管肺泡获得的人PAM中的毒性机制 从职业中的工人灌洗，暴露于钒化合物和非 - 吸烟，不暴露的人类志愿者。 这些细胞的评估将 专注于我们其他特定目标中定义的机制，以便所有人 我们的研究将在超级基金站点对人类接触进行建模。 相关性 我们与项目5的研究将使我们能够直接关联 我们的机械性发现与人体暴露状况。 我们将 使用Zeiss CEM902电子显微镜的电子能量损失技术 用于量化和直接视觉相关性的元素定位 细胞细胞质内的病理作用。 生化， 药理学和分子方法将用于定义机制 毒性/这些复杂技术的新颖应用 我们提出的研究将为细胞内剂量 - 钒化合物毒性的反应关系和机制。