CEREBRAL OXYGEN TRANSPORT WITH STABILIZED CELL FREE HEMOGLOBIN

稳定的无细胞血红蛋白的脑氧运输

• 批准号: 5213971
• 负责人: RAYMOND C KOEHLER
• 金额: --
• 依托单位国家: 美国
• 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/5213971
• 关键词: albumins; amine oxidoreductase; anemia; arterioles; autoradiography; blood brain barrier; blood cell count; blood treatment; cats; cell free system; cerebral ischemia /hypoxia; electroencephalography; hemoglobin; high energy compound; infrared spectrometry; nitric oxide; nuclear magnetic resonance spectroscopy; oxygen transport; pia mater; respiratory oxygen; vasodilators

Oxygen transport to the brain is ordinarily well regulated in that decreases in arterial 02 content associated with anemic, hypoxic and CO hypoxia result in reciprocal increases in cerebral blood flow. In the case of anemia, it remains unclear if increased cerebral blood flow is a consequence of decreased viscosity or 02 availability. Differentiating these mechanisms is important because anemia is a common form of clinical hypoxia, hemodilution is routinely employed during cardiopulmonary bypass, and positive evidence of reduced infarction with hemodilution in experimental focal cerebral ischemia has prompted clinical trials in patients with stroke. Exchange transfusion with red cell free oxyhemoglobin provides a unique physiological tool for dissociating effects of 02 carrying capacity from viscosity when hematocrit is reduced. Chemical stabilization of hemoglobin preserves its tetrameric form and 02 binding cooperatively, and increases its circulating half- life compared to untreated hemoglobin. Our overall goal is to determine the mechanism of hematocrit-induced changes in the cerebral circulation under normal and ischemic conditions in anesthetized cats. First, we will determine the effect of reducing hematocrit with or without reductions in O2 carrying capacity on cerebral blood flow, cerebral 02 extraction and cerebral tissue oxyhemoglobin content, measured by near-infrared spectroscopy in vivo. After reducing hematocrit with free oxyhemoglobin or albumin, we will determine how well cerebral O2 transport is regulated when arterial PO2 is reduced. Second, we will show whether circulating free hemoglobin alters endothelial dependent and independent pial arteriolar dilation in vivo or alters blood-brain barrier permeability. Third, by using 31P magnetic resonance spectroscopy to measure brain high energy phosphates and intracellular pH, we will demonstrate if the threshold for producing cerebral ischemia is improved by reducing hematocrit and oxyhemoglobin affinity to augment O2 distribution and unloading. Fourth, we will determine whether free hemoglobin transfusion reduces the progression of cerebral infarction during middle cerebral artery occlusion by increasing tissue oxygenation as a consequence of increased perfusion of free hemoglobin in the ischemic territory. New insights derived from transfusions with oxyhemoglobin of different O2 affinities will distinguish viscosity, O2 carrying capacity, and O2 unloading mechanisms in the regulation of cerebral O2 transport during anemia and ischemia and will provide new strategies for increasing cerebral O2 availability.

向大脑的氧气输送通常受到良好的调节 与贫血、缺氧和 CO 相关的动脉 02 含量减少 缺氧导致脑血流量相应增加。 在 在贫血的情况下，尚不清楚脑血流量增加是否与贫血有关。 粘度降低或 02 可用性降低的结果。 差异化 这些机制很重要，因为贫血是一种常见的临床形式 缺氧，心肺检查时常规采用血液稀释 搭桥术，以及通过血液稀释减少梗塞的积极证据 实验性局灶性脑缺血促使临床试验 中风患者。 无红细胞换血 氧合血红蛋白为解离提供了独特的生理工具 当血细胞比容为 02 时，粘度对 02 承载能力的影响 减少。 血红蛋白的化学稳定性保留了其四聚体 形式和02协同结合，并增加其循环半- 与未经处理的血红蛋白相比的寿命。 我们的总体目标是确定血细胞比容诱导的机制 正常和缺血条件下脑循环的变化 在麻醉猫中。 首先，我们要确定减少的效果 血细胞比容伴或不伴脑部携氧能力降低 血流量、脑02提取和脑组织氧合血红蛋白 含量，通过体内近红外光谱测量。 减少后 血细胞比容与游离氧合血红蛋白或白蛋白，我们将确定效果如何 当动脉 PO2 减少时，脑 O2 运输受到调节。 第二， 我们将证明循环游离血红蛋白是否会改变内皮细胞 体内依赖性和独立性软脑膜小动脉扩张或改变 血脑屏障的通透性。 三、利用31P磁共振 光谱法测量大脑高能磷酸盐和细胞内 pH值，我们将证明是否产生脑缺血的阈值 通过降低血细胞比容和氧合血红蛋白亲和力来增强 O2分配和卸载。 四、我们会判断是否免费 血红蛋白输注可减缓脑梗塞的进展 在大脑中动脉闭塞期间通过增加组织氧合 由于游离血红蛋白灌注增加 缺血区。 来自输血的新见解 不同O2亲和力的氧合血红蛋白会区分粘度，O2 承载能力和 O2 卸载机制的调节 贫血和缺血期间的脑氧运输，将提供新的 增加脑 O2 可用性的策略。