TRACE ELEMENT DYNAMICS IN THE VERTEBRATE EYE

铁(Fe)的眼睛毒性已被清楚地记录在与 眼内含铁异物对眼球的影响 大出血。现在有越来越多的证据表明铁 作为眼部炎症反应的一个组成部分，并与 组织损伤。过去所做的大部分工作都集中在 铁引起的组织学和视网膜电信号改变。这些实验 在本提案中描述的是旨在将生化、 铁毒性的结构和功能研究，并提供新的 深入了解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游离的能力。 激进的反应。在正常的生理条件下，铁是结合的 与蛋白质结合，不能催化自由基的形成。然而，铁可以 在病理条件下从其结合蛋白中释放出来，并可以 然后催化这些反应。在这个实验室正在进行的一个项目中 已开发出测定总铁结合态Fe的方法 容量和眼内液(IOF)中的“游离”催化铁和 血浆。在一个实验模型中，炎症患者体内的铁浓度 IOF是未发炎对照组的20多倍 眼睛。此外，在发炎的IOF中还发现了“游离”的催化铁。 在这项建议中，“游离”铁的存在与 增加铁从其表面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 将使用眼部炎症的内毒素模型来确定 兔子。组织损伤参数将包括 视网膜电信号、玻璃体液化和视网膜脂质过氧化。 在一组相关的实验中，铁将被注入玻璃体内 确定其破坏性影响的阈值水平。的影响 铁络合剂去铁胺与内源抗氧化剂铁结合 蛋白质转铁蛋白也将被探索。在所有计划的 实验研究了IOF中“游离铁”的量与 炎症反应的程度与IOF生化变化 眼睛的结构和功能将被确定。很可能是 铁在生物化学变化中作用的进一步阐明 在眼部炎症期间将导致治疗的进展 这种眼部病变的治疗。

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.