LUNG METABOLISM--MULTIPLE INDICATOR DILUTION

描述(申请人摘要)：该计划的目标是 发展无损评估的实验和理论基础 肺的新陈代谢状态。此续订申请基于 前提是有关肺细胞氧化还原状态的信息很重要 以评估肺对生理和病理生理学的反应 强调，两类氧化还原活性化合物将特别 可用作多指示剂稀释、MID、探头以实现此目的 信息：1)细胞无谓的电子受体，在 通过肺部的毛细血管内皮细胞表面，以及2)细胞 意思是电子供体，在通过肺部的过程中，进入肺部 它们可以被各种机制氧化的组织。中的变化 伴随着氧化还原状态的变化的物理化学性质 这些探头影响它们的光学性质，使其被氧化和还原 可区分的形式，以及它们穿过细胞膜的倾向， 改变了它们通过肺部的时间进程。具体目标 用于1)确定包含哪些有关肺代谢功能的信息 在静脉流出物浓度与时间的关系中获得以下数据 这些探头通过肺部，以及2)确定探头 肺内的还原和/或氧化被以下条件改变 在一定程度上改变肺细胞的氧化还原状态 可以用来评估肺的氧化还原状态 组织。一般的方法将是测量一个人的肺处置 从这两类中选择的一组指示器探头，以及一些 肺组织和血管的其他相关方面的其他指标 功能。肺部将使用代谢抑制剂和氧自由基进行治疗 清道夫，被选来帮助识别探测器涉及的机制 性情。初步研究将使用分离的大鼠肺进行， 其中某些重要的变量可以被操纵为有利的。这些 研究将包括正常大鼠和暴露于压力下的大鼠的肺。 已知或怀疑会影响肺部氧化还原状态(例如，高氧、低氧和 脂多糖治疗)。将开发出数学模型， 提供了一种方法来评估关于探针布置和 估计能够揭示过程贡献程度的参数 当肺部生物学改变时，探针的配置发生了变化。最后， 实验和模型开发将应用于 麻醉兔暴露于相似的应激状态下的体内评估 适用性。

DESCRIPTION (Applicant's abstract): The objectives of this program are to develop the experimental and theoretical basis for non-destructive evaluation of the metabolic status of the lung. This renewal application is based on the premise that information about the redox status of the lung cells is important for evaluating the lung response to physiological and pathophysiological stresses, and that two classes of redox active compounds will be particularly useful as multiple indicator dilution, MID, probes for obtaining this information: 1) cell impermeant electron acceptors that are reduced at the capillary endothelial surface on passage through the lungs, and 2) cell permeant electron donors that, during passage through the lungs, enter the lung tissue wherein they can be oxidized by various mechanisms. The changes in physical-chemical properties that accompany the changes in the redox state of these probes affects their optical properties, making the oxidized and reduced forms distinguishable, and their propensity for passing through cell membranes, altering the time course for their passage through the lungs. The Specific Aims are to 1) determine what information about lung metabolic function is contained in the venous effluent concentration versus time data obtained following passage of these probes through the lungs, and 2) determine whether probe reduction and/or oxidation within the lung are modified by conditions that alter the redox status of lung cells to the extent that the information contained in the data can be used to evaluate the redox status of the lung tissue. The general approach will be to measure the pulmonary disposition of a group of indicator probes chosen from these two classes, along with some additional indicators for other relevant aspects of lung tissue and vascular function. Lungs will be treated with metabolic inhibitors and oxygen radical scavengers, chosen to help identify the mechanisms involved in probe disposition. Initial studies will be carried out using isolated rat lungs, wherein certain important variables can be manipulated to advantage. These studies will include lungs from normal rats and from rats exposed to stresses known or suspected to affect lung redox status (e.g., hyperoxia, hypoxia, and lipopolysaccharide treatment). Mathematical models will be developed that provide a means for evaluating hypotheses regarding probe disposition and for estimating parameters that can reveal the extent to which a process contributes to a change in probe disposition when lung biology has been altered. Finally, the experimental and model development will be applied to studies in anesthetized rabbits exposed to similar stresses to evaluate in vivo applicability.