Microvascular effects of surface decorated hemoglobins

表面修饰血红蛋白的微血管效应

• 批准号: 6654249
• 负责人: Marcos Intaglietta
• 金额: $ 38.74万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-05 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6654249
• 关键词: biomaterial development /preparation; biomaterial evaluation; biotechnology; blood /plasma substitute; blood chemistry; blood flow measurement; blood viscosity; endothelin; hamsters; hemodynamics; hemoglobin; hemorrhagic shock; microcirculation; nitric oxide; oxygen transport; plasma; polyethylene glycols; prostacyclins; tissue /cell culture; vascular endothelium; vasoconstriction; vasomotion

DESCRIPTION (provided by applicant): We propose to determine the mechanisms that cause vasoconstriction when cell free hemoglobins are introduced into the circulation as the O2 carrier of an O2-carrying plasma expander (OCPE) by studying the vascular effects produced by polyethylene glycol (PEG) surface decorated hemoglobins (HbS) developed in this program. We will study the presser response to top loads of various formulations and quantify the reactions of the microcirculation in the hamster skinfold model, which can be studied without anesthesia, in the awake condition for periods of up to 2 weeks. The principal microvascular parameters to be evaluated in vivo are functional capillary density and intravascular oxygen tension distribution. Tests will analyze different hypothesis on the genesis of vasoactivity due to molecular hemoglobin in the circulation, namely: 1) NO scavenging by hemoglobin; 2) lowered viscosity in hemodilution, leading to lowered shear stress and production of endothelial relaxing factors; 3) Increased facilitated diffusion and O2 autoregulation by oxyhemoglobin; and, 4) Extent of hemoglobin surface shielding by PEG molecules. Efficacy of the OCPEs will be determined in conditions of isovolemic hemodilution and hemorrhagic shock. An effective OCPE must also insure sufficiently elevated blood viscosity, which is necessary for the maintenance of adequate microvascular function, and condition that can be obtained with PEG-Hbs. In hemodilution these molecules increase plasma viscosity, causing redistribution of hydraulic pressure in the circulation, decreasing systemic viscosity dependent pressure losses and increasing peripheral resistance. Additionally the O2 dissociation curve for these modified hemoglobins should be left shifted, so O2 release occurs only in anoxic regions and not from arterioles and where tissue oxygenation is adequate. Our goal is to obtain an understanding of vasoactivity in support of OCPE development that prioritizes maintenance of microvascular function in terms of capillary perfusion, which is as critical for tissue survival as adequate oxygenation, by using methods for the analysis at the cellular microscopic level, where blood performs its vital functions.

描述（由申请人提供）： 我们建议确定无细胞时引起血管收缩的机制 血红蛋白作为载氧血浆的载氧体引入循环系统 通过研究聚乙二醇 (PEG) 产生的血管效应来扩展 (OCPE) 该项目中开发了表面修饰血红蛋白 (HbS)。我们将研究压机 对各种配方的最高负荷的响应并量化微循环的反应 在仓鼠皮褶模型中，无需麻醉即可在清醒状态下进行研究 为期长达 2 周。体内评估的主要微血管参数 是功能性毛细血管密度和血管内氧分压分布。测试将分析 关于分子血红蛋白引起的血管活性起源的不同假设 循环，即： 1）血红蛋白清除NO； 2) 降低血液稀释的粘度， 导致剪切应力降低和内皮松弛因子的产生； 3）增加 通过氧合血红蛋白促进扩散和 O2 自动调节；以及，4) 血红蛋白的程度 PEG分子的表面屏蔽。 OCPE 的功效将在以下条件下确定： 等容血液稀释和失血性休克。有效的 OCPE 还必须确保 充分升高血液粘度，这是维持足够的血液粘度所必需的 可以用 PEG-Hbs 获得的微血管功能和状况。在血液稀释中 这些分子增加血浆粘度，导致液体压力重新分布 循环，减少系统粘度依赖的压力损失并增加外周 反抗。此外，这些修饰的血红蛋白的 O2 解离曲线应保留 转移，因此 O2 释放仅发生在缺氧区域，而不是来自小动脉和组织 氧合充足。我们的目标是了解血管活动以支持 OCPE的开发优先考虑毛细血管方面的微血管功能 灌注，这对于组织存活与充分氧合同样重要，通过使用以下方法： 在细胞微观水平上进行分析，血液在细胞微观水平上发挥其重要功能。