KINETIC STUDY OF INFLAMMATION-INDUCED HYPORETINEMIA

描述(由申请人提供)： 这项建议的长期目标是检查炎症引起的低视网膜炎对肝脏维生素A(VA)储存和视网膜功能的影响。先前已经证明，在急性炎症期间，肝脏视黄醇结合蛋白(RBP)和转甲状腺素(TTR)的合成减少，导致血浆视黄醇浓度降低(低视黄素血症)。目前研究的前提是，低视黄素血症如果持续，将损害VA在肝组织和非肝组织之间的分布。提出了两项研究。首先，将使用动力学数据和基于模型的隔室分析来评估急性炎症期间血浆视黄醇的分布和动力学行为。含有标记视黄醇的血浆将被静脉注射给维生素A缺乏的大鼠，循环示踪剂浓度将被允许达到一个末端斜率；然后，系统将被来自铜绿假单胞菌的脂多糖诱导急性炎症而扰动，循环示踪剂浓度将被允许达到一个新的末端斜率。Tracee和Tracee数据将从血浆、肝脏、肾脏、眼球和剩余的身体中收集。将使用模拟、分析和建模(SAAM)计算机程序进行基于模型的隔室分析，以调整模型参数以最好地符合数据。基于这一分析，将产生一些假设，以解释血浆、肝脏和肾脏之间视黄醇池的动态变化，以及这些池中的变化如何导致视网膜VA降低。在第二项研究中，将建立慢性炎症动物模型，持续给予重组人白细胞介素6(RhlL6)，以评估低视黄素血症对视网膜功能的影响。轻度缺乏维生素A的大鼠通过渗透压泵给药7~14d，用高效液相色谱法测定肝和非肝组织中维生素A的浓度。在实验的第一周和第二周，将通过视网膜电图仪检查视网膜功能。这一信息将有助于在炎症期间循环中存在低浓度视黄醇的情况下重新定义VA状态。此外，这些方法的应用和慢性炎症模型的发展将促进对铁和锌等同样受到炎症影响的其他微量营养素的研究。

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to examine the consequences of inflammation-induced hyporetinemia on hepatic vitamin A (VA) stores and retinal function. Previously, it has been demonstrated that the synthesis of hepatic retinol-binding protein (RBP) and transthyretin (TTR) are reduced during acute inflammation causing a reduction of plasma retinol concentrations (hyporetinemia). The premise of the current study is that hyporetinemia, if prolonged, will impair the distribution of VA between hepatic and non-hepatic tissues. Two studies are proposed. In the first, the distribution and kinetic behavior of plasma retinol will be evaluated using kinetic data and model-based compartmental analysis during acute inflammation. Plasma containing labeled retinol {[3H]retinoI-RBP-TTR} will be injected iv to marginally-VA deficient rats and circulating tracer concentrations will be allowed to reach a terminal slope; then, the system will be perturbed by inducing acute inflammation with lipopolysaccharide from P. aeruginosa, and circulating tracer concentrations will be allowed to reach a new terminal slope. Tracer and tracee data will be collected from plasma, liver, kidneys, eyeballs and remaining carcass. Model-based compartmental analysis using the Simulation, Analysis and Modeling (SAAM) computer program will be used to adjust model parameters to best fit the data. Based on this analysis, hypotheses will be generated to explain the dynamics of pools of retinol among plasma, liver and kidneys, and how alterations in these pools may contribute to decrease retinal VA. in the second study, an animal model of chronic inflammation will be developed with continuous administration of recombinant human intedeukin-6 (rhlL6) to assess the effect of hyporetinemia on retinal function. Marginally-VA deficient rats will receive rhlL6 or saline by means of osmotic pumps for 7 to 14 d. VA concentrations in hepatic and non-hepatic tissues will be determined by HPLC at various times. Retinal function will be examined by means of electroretinography during the first and second weeks of experimentation. This information will help in re-defining VA status in the presence of low circulating retinol concentrations during inflammation. In addition, the application of these methods and the development of a model of chronic inflammation will foster research on other micronutrients like iron and zinc that are similarly affected by inflammation.