Inhibition of Lipid Peroxidation in Subarachnoid Hemorrage

蛛网膜下腔出血中脂质过氧化的抑制

基本信息

批准号：
8489125
负责人：
L Jackson Roberts, II
金额：
$ 49.45万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8489125
关键词：
Accounting Acetaminophen Acetylcysteine Acute Renal Failure with Renal Papillary Necrosis Adult Amino Acids Animal Model Antioxidants Attenuated Biological Markers Brain Cardiac Surgery procedures Cardiopulmonary Bypass Cells Cellular Membrane Cerebrospinal Fluid Cessation of life Clinical Trials Complication Development Disease Dose Electron Transport Environment F2-Isoprostanes Functional disorder Glutathione Hemeproteins Hemoglobin Hemolysis Hemorrhage Human Hydrogen Peroxide In Vitro Injury Injury to Kidney Instruction Investigation Isoprostanes Kidney Kidney Failure Lead Lipid Peroxidation Lipid Peroxides Lipids Measurement Modeling Morbidity - disease rate Myoglobin Neurologic Neurological outcome Oryctolagus cuniculus Outcome Study Oxidation-Reduction Oxidative Stress Patients Peroxidases Pharmaceutical Preparations Pharmacology Pilot Projects Plasma Prodrugs Prostaglandin-Endoperoxide Synthase Proteins Randomized Rattus Recovery Regimen Renal function Research Rhabdomyolysis Severities Stroke Subarachnoid Hemorrhage Testing Therapeutic Time Toxicology Vasoconstrictor Agents Vasospasm base disability glutathione peroxidase human disease improved in vivo inhibitor/antagonist mortality oxidative damage peroxidation prevent prospective randomized trial

项目摘要

PROJECT SUMMARY (See instructions): Hemeprotein-catalyzed lipid peroxidation contributes to the pathophysiology of diseases in which myoglobin and hemoglobin are released from the antioxidant environment of cells. These include a major contribution of myoglobin-catalyzed lipid peroxidation to the renal failure produced by rhabdomyolysis. Lipid peroxidation induced by hemoglobin is correlated with the pathophysiology of subarachnoid hemorrhage. Among the products of lipid peroxidation are the F2-isoprostanes, which are highly potent vasoconstrictors. We have demonstrated that lipid peroxidation catalyzed by the peroxidase-like function of oxidized hemoproteins is inhibited by acetaminophen. In a rat model of rhabdomyolysis in which Fa-isoprostanes generated intrarenally contribute to the renal failure, acetaminophen significantly reduced lipid peroxidation and markedly decreased the extent of renal failure. In a rabbit model of subarachnoid hemorrhage, an acetaminophen prodrug significantly reduced levels of F2-isoprostanes. Based on this evidence, the effect of acetaminophen will be evaluated in subarachnoid hemorrhage, in which evidence of lipid peroxidation correlates with time of delayed vasospasm and with severity of neurological deficits. This will be a pilot study in which acetaminophen based regimens will be tested for their ability to reduce lipid peroxidation assessed by measurement of F2-isoprostane levels in cerebrospinal fluid. Secondary endpoints will include vasospasm, as well as neurological outcome, but this pilot study is not powered for these. The results could provide a basis for a larger outcome study, and a rationale for development of even more potent regimens for inhibiting hemoprotein-catalyzed lipid peroxidation in subarachnoid hemorrhage. Acute kidney injury occurs in up to 30% of patients who undergo cardiac surgery with cardiopulmonary bypass, and is an independent predictor of morbidity and mortality. Elevated plasma levels of free hemoglobin and myoglobin correlate with acute kidney injury, and increased levels of the lipid peroxidation biomarkers, F2-isoprostanes and isofurans, are also associated with acute kidney injury. The concerted evidence supports a hypothesis that hemeprotein-catalyzed peroxidation of renal lipids is a major and potentially modifiable contributor to the acute kidney injury. Accordingly, a proof-of-concept investigation to assess the effect of acetaminophen on F2-isoprostanes and isofurans in patients undergoing cardiac surgery with cardiopulmonary bypass is proposed. Evidence that acetaminophen inhibited lipid peroxidation in these patients would provide a rationale for an outcome study evaluating its effect on acute kidney injury in these patients.

项目摘要（参见说明）：血红素蛋白催化的脂质过氧化有助于肌红蛋白和血红蛋白从细胞的抗氧化环境中释放的疾病的病理生理学。其中包括肌红蛋白催化的脂质过氧化对横纹肌溶解引起的肾功能衰竭的主要贡献。血红蛋白诱导的脂质过氧化与蛛网膜下腔出血的病理生理学相关。脂质过氧化的产物包括 F2-异前列腺素，它是高效的血管收缩剂。我们已经证明，对乙酰氨基酚可以抑制由氧化血红素蛋白的过氧化物酶样功能催化的脂质过氧化反应。在横纹肌溶解症大鼠模型中，肾内产生的 Fa-异前列烷导致肾衰竭，对乙酰氨基酚显着减少脂质过氧化，并显着降低肾衰竭的程度。在兔蛛网膜下腔出血模型中，对乙酰氨基酚前药显着降低了 F2-异前列腺素的水平。基于这一证据，将对乙酰氨基酚在蛛网膜下腔出血中的作用进行评估，其中脂质过氧化的证据与延迟性血管痉挛的时间和神经功能缺损的严重程度相关。这将是一项试点研究其中将测试基于对乙酰氨基酚的治疗方案减少脂质过氧化的能力，通过测量脑脊液中的 F2-异前列烷水平来评估。次要终点将包括血管痉挛以及神经系统结果，但这项试点研究并不针对这些终点。这些结果可以为更大规模的结果研究提供基础，并为开发更有效的抑制蛛网膜下腔出血中血红蛋白催化的脂质过氧化的方案提供依据。在接受体外循环心脏手术的患者中，高达 30% 的患者会出现急性肾损伤，这是一种严重的并发症。发病率和死亡率的独立预测因子。血浆游离血红蛋白和肌红蛋白水平升高与急性肾损伤相关，脂质过氧化生物标志物 F2-异前列腺素和异呋喃水平升高也与急性肾损伤相关。一致的证据支持这样的假设：血红素蛋白催化的肾脂质过氧化是急性肾损伤的主要且可能可改变的因素。因此，建议进行一项概念验证研究，以评估对乙酰氨基酚对接受体外循环心脏手术的患者中 F2-异前列腺素和异呋喃的影响。对乙酰氨基酚抑制这些患者的脂质过氧化的证据将为评估其对这些患者急性肾损伤的影响的结果研究提供依据。