Lung Metabolism: Multiple Indicator Dilution

肺代谢：多指标稀释

基本信息

批准号：
7319030
负责人：
SAID H AUDI
金额：
$ 25.57万
依托单位：
MARQUETTE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1979
资助国家：
美国
起止时间：
1979-08-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7319030
关键词：
Accounting Adult Respiratory Distress Syndrome Adverse effects Air Angiography Animal Model Antioxidants Appearance Area Blood Blood Vessels Blood capillaries Bolus Infusion Cell surface Cells Cellular biology Chronic Obstructive Airway Disease Class Coenzymes Complex Data Development Dyes Electron Transport Electron Transport Complex III Electrons Endothelial Cells Environment Enzyme Kinetics Enzymes Exposure to Failure Future Goals Heterogeneity Human Hyperoxia Hypoxemia In Vitro Infusion procedures Injection of therapeutic agent Kinetics Lung Measurement Measures Membrane Metabolism Methods Methylene blue Mitochondria Modeling Molecular Weight NAD(P)H Dehydrogenase (Quinone)NAD(P)H dehydrogenase (quinone) 1, human NADH dehydrogenase (ubiquinone)NQO1 gene Oxidants Oxidation-Reduction Oxidoreductase Oxygen Patients Perfusion Physiologic pulse Physiological Plasma Plasma Proteins Play Pneumonia Predisposition Property Proteins Protocols documentation Pulmonary Circulation Pulmonary artery structure Pulse taking Qi Quantitative Evaluations Quinone Reductases Quinones Rate Rattus Research Design Research Personnel Respiratory physiology Rodent Roentgen Rays Role Secondary to Severities Structure of parenchyma of lung Surface System Time Tissues Toxic effect Ubiquinone Venous base benzoquinone blue dextran capillary concept cytochrome c day duroquinone electron donor genetic manipulation indexing inhibitor/antagonist insight lung injury mathematical model programs therapeutic target tool ubiquinol

项目摘要

DESCRIPTION (provided by applicant): A common initial treatment for hypoxemia in patients with lung failure secondary to chronic obstructive pulmonary diseases, pneumonia, or adult respiratory distress syndrome is elevated 02 therapy (hyperoxia). However, prolonged exposure to hyperoxia causes lung injury. The rat model of hyperoxic lung injury mimics several aspects of lung O2 toxicity observed clinically and is unique in that exposure to 85% O2 for 7 days confers tolerance to the otherwise lethal effects of 100% O2. Conversely, rats exposed to 60% O2 for 7 days become more susceptible to 100% O2. Our long-term goal is to elucidate the mechanisms of tolerance and susceptibility to 100% O2. Studies have demonstrated hyperoxia-induced changes in the activities of redox enzymes, predominantly in lung tissue homogenates, and have suggested that redox enzymes play a role in rat tolerance/susceptibility to 100% O2. However, the results of these in vitro studies do not necessarily predict hyperoxia-induced changes in the activities of redox enzymes in an intact functioning lung. We propose that measurements of the activities of redox enzymes in intact lungs of rats exposed to 60% O2 and 85% O2 can provide critical insights into the role of these enzymes in conferring tolerance or susceptibility to 100% O2. Thus, the specific aims are: 1) Develop an experimental protocol and a mathematical model for quantitative evaluation of the activities of redox enzymes in intact lungs. 2) Use the tools developed under specific aim 1 to determine the effects of 7-day rat exposure to 60% O2 and 85% O2 on the activities of redox enzymes in intact lungs. The general approach will be to measure the venous outflow blood concentrations of probes for targeted redox enzymes during the injection of these probes into the arterial inlet of isolated perfused lungs of rats exposed to room air, 60% O2 or 85% O2. Mathematical modeling will be used to interpret the resulting data and to determine the activities of the targeted redox enzymes in intact lungs. Statistical analysis will determine which redox enzymes are differentially altered by a 7-day exposure to 60% O2 and 85% O2. Demonstration that the activity of a redox enzyme in intact lungs is differentially altered by exposure to 60% O2 and 85% 02 would be suggestive of a role in conferring susceptibility or tolerance to 100% O2. Such results will provide targets for future mechanistic studies designed to evaluate the utility of the differentially altered redox enzymes as potential therapeutic targets for protection from O2 toxicity.

描述（由申请人提供）：对于慢性阻塞性肺部疾病，肺炎或成人呼吸窘迫综合征的肺部失败患者的低氧血症的常见初始治疗方法是02治疗（Hyperoxia）。但是，长时间暴露于高氧会导致肺损伤。高氧性肺损伤的大鼠模型模仿了临床上观察到的肺O2毒性的几个方面，并且在7天暴露于85％O2的情况下是独一无二的，这赋予了对100％O2的致命作用的容忍度。相反，暴露于60％O2持续7天的大鼠更容易受到100％O2的影响。我们的长期目标是阐明对100％O2的耐受性和易感性的机制。研究表明，高氧诱导的氧化还原酶活性变化，主要是在肺组织匀浆中，并提出氧化还原酶在大鼠的耐受性/易感性中对100％O2发挥作用。但是，这些体外研究的结果不一定预测高氧诱导的氧化还原酶在完整功能肺中的活性变化。我们建议测量暴露于60％O2和85％O2的大鼠完整肺中氧化还原酶的活性，可以为这些酶在赋予耐受性或对100％O2的易感性中的作用提供关键见解。因此，具体目的是：1）开发一个实验方案和一个数学模型，用于定量评估完整肺中氧化还原酶的活性。 2）使用特定目标1开发的工具来确定7天大鼠暴露于60％O2和85％O2对完整肺氧化还原酶活性的影响。一般方法是在将这些探针注射到暴露于房间空气的大鼠的动脉入口中，测量靶向氧化还原酶的静脉流出的血液浓度，用于靶向氧化还原酶。数学建模将用于解释所得数据并确定完整肺中靶向的氧化还原酶的活性。统计分析将通过7天的O2和85％O2的7天暴露来确定哪些氧化还原酶被差异化。证明氧化还原酶在完整肺中的活性通过暴露于60％O2和85％02的差异改变将暗示在赋予易感性或对100％O2的耐受性中的作用。这样的结果将为未来的机械研究提供目标，旨在评估差异改变的氧化还原酶的实用性，作为保护侵害O2毒性的潜在治疗靶标。