LUNG METABOLISM--MULTIPLE INDICATOR DILUTION

描述（申请人摘要）：本计划的目标是 为非破坏性评估提供实验和理论基础 肺的代谢状态。此更新申请基于 前提是关于肺细胞的氧化还原状态的信息是重要的 用于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，探针，用于获得这种 信息：1）在细胞中还原的细胞不渗透的电子受体 通过肺时的毛细血管内皮表面，和2）细胞 在通过肺的过程中进入肺的渗透性电子供体 组织，其中它们可以通过各种机制被氧化。的变化 物理化学性质，伴随着氧化还原状态的变化， 这些探针会影响它们的光学性质， 形态可区分，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 是1）确定包含哪些关于肺代谢功能的信息 在以下获得的静脉流出物浓度与时间数据中 这些探针通过肺部，以及2）确定探针是否 肺内的还原和/或氧化被以下条件改变， 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肺处置的一个 从这两类中选择的一组指示探针，沿着一些 肺组织和血管的其他相关方面的额外指标 功能肺部将接受代谢抑制剂和氧自由基治疗 清道夫，选择来帮助确定参与探测机制 处分初步研究将使用离体大鼠肺进行， 其中某些重要的变量可以被有利地操纵。这些 研究将包括正常大鼠和暴露于压力的大鼠的肺 已知或怀疑影响肺氧化还原状态（例如，高氧、缺氧和 脂多糖处理）。将开发数学模型， 提供一种用于评估关于探针布置的假设的方法， 估计可以揭示过程贡献程度的参数 当肺部生物学改变时，探头布置发生变化。最后， 实验和模型开发将应用于以下研究： 暴露于类似应力的麻醉家兔，以进行体内评价 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.