TRACE ELEMENT DYNAMICS IN THE VERTEBRATE EYE

铁（Fe）的眼毒性已被明确记录， 含铁眼内异物的影响， 出血 现在有越来越多的证据表明铁 作为眼部炎症反应的组成部分， 组织损伤 过去所做的大部分工作都集中在 组织学和视网膜电图改变。 实验 在该提案中描述的是设计成整合生物化学， 铁毒性结构和功能的研究，并提供新的 铁在眼部炎症反应中的作用。 铁的毒性作用可能是由于其催化自由基的能力， 激进的反应 在正常生理条件下， 不能催化自由基的形成。 但是，Fe可以 在病理条件下从其结合蛋白中释放， 然后催化这些反应。 在这个实验室正在进行的项目中 已经开发了用于测量Fe、总铁结合的方法 容量和眼内液（IOF）中的“游离”催化Fe， 等离子体 在一个实验模型中， IOFs比未发炎的对照组增加了20倍以上 眼睛 此外，在发炎的IOFs中发现了“游离”催化Fe。 在这个提议中，“游离”Fe的存在与 增加Fe从其释放的可能性的条件 结合蛋白对眼部炎症和组织损伤参数的影响 将使用眼炎症的内毒素模型测定， 家兔 组织损伤参数将包括 视网膜电图、玻璃体液化和视网膜脂质过氧化。 在一组相关的实验中，将玻璃体内注射Fe， 确定其破坏性影响的阈值水平。 的影响 铁螯合剂去铁胺和内源性抗氧化剂铁结合 还将探索蛋白质转铁蛋白。 在所有的计划中， 实验IOFs中“游离”Fe的量之间的关系， 炎症反应的程度和IOF生化变化 并确定眼睛的结构和功能。 很可能 进一步阐明了铁在生物化学变化中的作用， 将导致治疗进展， 治疗这种眼部疾病。

The ocular toxicity of iron (Fe) has been clearly documented in relation to the effects of Fe containing intraocular foreign bodies and hemorrhage. There is now a growing body of evidence which implicates Fe as an integral part of the ocular inflammatory response and associated tissue damage. Much of the work done in the past has centered on histologic and electroretinogram changes induced by Fe. The experiments described in this proposal are designed to integrate biochemical, structural and functional studies of Fe toxicity and to provide new insights into Fe's role in the ocular inflammatory response. The toxic effects of Fe are likely due to its ability to catalyze free radical reactions. Under normal physiologic circumstances, Fe is bound to proteins and cannot catalyze free radical formation. However, Fe can be released from its binding proteins in pathological conditions and can then catalyze these reactions. In an ongoing project in this laboratory methods have been developed for measurement of Fe, total-iron-binding capacity, and "free" catalytic Fe in the intraocular fluids (IOFs) and plasma. In an experimental model, the Fe concentration of the inflamed IOFs was increased more than 20 times that of the uninflamed control eyes. Furthermore, "free" catalytic Fe was found in the inflamed IOFs. In this proposal, the relationship between the presence of "free" Fe and the conditions which increase the likelihood of Fe's release from its binding proteins on parameters of ocular inflammation and tissue damage will be determined using the endotoxin model of ocular inflammation in rabbits. Tissue damage parameters will include changes in electroretinogram, vitreal liquefaction and retinal lipid peroxidation. In a related set of experiments, Fe will be injected intravitreally to determine the threshold level for its damaging effects. The effects of the Fe-chelator desferrioxamine and the endogenous antioxidant Fe-binding protein transferrin will also be explored. In all of the planned experiments the relationship between the amount of "free" Fe in the IOFs, the extent of the inflammatory response and changes in IOF biochemistry and ocular structure and function will be determined. It is likely that further elucidation of Fe's role in the biochemical changes which occur during ocular inflammation will lead to therapeutic advances in the treatment of this ocular pathology.