In Vivo Detection of Free Radical Generation

自由基产生的体内检测

• 批准号: 8149028
• 负责人: RONALD P MASON
• 金额: $ 79.61万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8149028
• 关键词: Acetone; Data; Detection; Diabetes Mellitus; Dimethyl Sulfoxide; Disease; Endotoxins; Free Radicals; Generations; Inflammatory Response; Mediator of activation protein; in vivo; nitration

The goal of this study is to better understand the involvement of free radicals in the mechanism of inflammatory responses at all levels from molecular/cellular biology to whole animals and, ultimately, to humans, and to advance both basic and clinical research in free radical-mediated disease processes. Overall this project tested the hypotheses that: 1) free radicals are causative molecules in the complex pathogenesis of diabetes mellitus and inflammation; and 2) specific biochemical pathways are involved in triggering generation of free radicals that may act as mediators and/or modulators of inflammatory reactions associated with human disease. In this study, free radical generation in vivo caused by endotoxin, exotoxin, streptozotocin, acetone and others has been shown in specific disease states of inflammation, pneumonia, diabetes, and ketosis. Research Accomplishments: i) Free Radical Intermediates in Diabetes Mellitus and Ketosis. We have provided ESR and immuno-spin trapping data for in vivo free radical formation as a mechanism that occurs in streptozotocin-induced diabetes and contributes to lipid peroxidation and protein nitration in the liver and kidneys. The studies demonstrated involvement of iNOS in hydroxyl radical-mediated lipid peroxidation since iNOS overexpression correlated with increased free radical production in the organs examined. In addition, we have shown that administration of acetone, a model of ketosis in diabetes, can also lead to protein oxidation and lipid peroxidation through a free radical-dependent mechanism also driven mainly by iNOS overexpression. ii) Free Radical Production in Inflammation. It has been demonstrated that free radical production in superantigen (SEB)-induced interstitial pneumonia (IP) depends on xanthine oxidase, iron and NO induction. It is concluded that macrophage toxicants, xanthine oxidase inhibitors, iron chelators, or inducible nitric oxide synthase inhibitors may be potential therapeutic agents against alveolitis and fibrosis in interstitial pneumonia iii)Free Radical Generation by Metals and Toxic Chemicals. Wide use of flame retardants can pose an environmental hazard so it is of interest to determine the mechanism of their toxicity. Of all the BFRs, 3,3',5,5'-tetrabromobisphenol A (TBBPA) is produced in the largest volume. The hydroxyl radical generated via the Fenton reaction from hydrogen peroxide reacts in vivo with DMSO to give the methyl radical, which is trapped by POBN. These observations suggest that the hepatotoxicity of TBBPA in rats may be due to the in vivo generation of the hydroxyl radical as a result of redox reactions involving the TBBPA metabolite 2,6-dibromohydroquinone and its corresponding semiquinone radical.

本研究的目的是更好地了解自由基参与炎症反应的机制，从分子/细胞生物学到整个动物，最终到人类，并推进自由基介导的疾病过程的基础和临床研究。总体而言，本项目验证了以下假设：1)自由基是糖尿病和炎症复杂发病机制中的致病分子；2)特定的生化途径参与触发自由基的产生，自由基可能作为与人类疾病相关的炎症反应的介质和/或调节剂。在本研究中，由内毒素、外毒素、链脲佐菌素、丙酮等引起的体内自由基生成已在炎症、肺炎、糖尿病、酮症等特定疾病状态中得到证实。