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Development of specific delivery system for anti-oxidant enzymes to inflammatory lesions

抗氧化酶针对炎症病变的特异性递送系统的开发

基本信息

批准号：
12672089
负责人：
KOSHIISHI Ichiro
金额：
$ 1.98万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12672089/
关键词：
in vivo ESR-CT spin probe free radical reactive oxygen species reactive nitrogen species redox balance ischemia reperfusion 活性酵素

项目摘要

Recently, it was generally demonstrated that activated neutrophils are responsible for the induction and development of inflammatory lesions accompanied with ischemia-reperfusion and several types of tissue damages, through the generation of hydroxyl radical and peroxynitrite from superoxide. The purpose of the present study is to prevent the generation of these substances via scavenging superoxide by anti-oxidant enzymes delivered to inflammatory lesions.Activated leukocytes induce acute tissue damage, so that these cells may release reactive oxygen species including superoxide just after attachment to the endothelial cell-lining. To dismutate superoxide into oxygen molecule and hydrogen peroxide, at first, we synthesized a conjugate of superoxide dismutase (SOD) with polyethylene glycol (PEG; MW, 5 kDa), and a conjugate of nitroxyl spin probes, SOD mimics, with PEG. Secondly, we synthesized nitroxyl spin probes conjugated with hyaluronan, which is a legand against the hyaluronan receptor (CD 44) on the cell surface of inflammatory cells.When these anti-oxidant substances, were subjected to the study for their in vivo behaviors, it was elucidated that these substances possess characters, remaining in the intravascular compartment and accumulating in the inflammatory lesion. Furthermore, we applied these substances to transient focal cerebral ischemia injury in mice. As a result, they significantly suppressed brain edema formation. Through these fact, the functional anti-oxidant polymers is thought to play a role in scavenging free radicals in inflammatory lesions.

最近，人们普遍证明，活化的中性粒细胞通过超氧化物产生羟自由基和过氧亚硝酸盐，负责诱导和发展伴随缺血再灌注和多种类型组织损伤的炎症病变。本研究的目的是通过递送到炎症病变处的抗氧化酶清除超氧化物来防止这些物质的产生。活化的白细胞会诱导急性组织损伤，因此这些细胞在附着在内皮细胞衬里后可能会释放包括超氧化物在内的活性氧。为了将超氧化物歧化为氧分子和过氧化氢，我们首先合成了超氧化物歧化酶（SOD）与聚乙二醇（PEG；MW，5 kDa）的缀合物，以及硝酰基自旋探针（SOD模拟物）与PEG的缀合物。其次，我们合成了与透明质酸缀合的硝酰基自旋探针，透明质酸是针对炎症细胞表面的透明质酸受体（CD 44）的标记。当对这些抗氧化物质进行体内行为研究时，发现这些物质具有保留在血管内并在炎症细胞中积累的特性。病变。此外，我们将这些物质应用于小鼠短暂性局灶性脑缺血损伤。结果，它们显着抑制了脑水肿的形成。通过这些事实，功能性抗氧化聚合物被认为在清除炎症病变中的自由基方面发挥作用。