KINETIC STUDY OF INFLAMMATION-INDUCED HYPORETINEMIA

描述（由申请人提供）：

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.