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.

氧气输送到大脑通常是很好的调节， 与贫血、缺氧和CO相关的动脉O2含量降低 缺氧导致脑血流量相互增加。 在 贫血的情况下，目前还不清楚，如果增加脑血流量， 这是粘度或O2可用性降低的结果。 区分 这些机制是重要的，因为贫血是一种常见的临床形式， 在心肺复苏期间， 旁路，以及血液稀释减少梗死的积极证据， 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 氧合血红蛋白提供了一种独特的生理工具， 当血细胞比容为 降低 血红蛋白的化学稳定化保留了其四聚体 形成和O2结合协同，并增加其循环半， 与未经治疗的血红蛋白相比。 我们的总体目标是确定红细胞压积诱导的 正常和缺血条件下脑循环的变化 在麻醉的猫身上。 首先，我们将确定减少的效果 红细胞压积伴或不伴脑组织载氧能力降低 血流量、脑O2提取和脑组织氧合血红蛋白 含量，通过近红外光谱法在体内测量。 还原后 红细胞压积与游离氧合血红蛋白或白蛋白，我们将确定 当动脉PO2降低时，脑O2运输受到调节。 第二、 我们将展示循环中的游离血红蛋白是否会改变内皮细胞的功能， 依赖性和独立性软膜小动脉扩张在体内或改变 血脑屏障通透性 第三，通过使用31P磁共振 光谱测量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提高 氧气分配和卸载。 第四，我们将确定是否免费 血红蛋白输注可减缓脑梗死的进展 在大脑中动脉闭塞期间通过增加组织氧合 作为增加灌注的游离血红蛋白在 局部缺血区域 从输血中获得的新见解 不同O2亲和力的氧合血红蛋白将区分粘度、O2 承载能力和O2卸载机制的调节， 贫血和缺血期间脑氧转运，并将提供新的 增加脑氧供应的策略。