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）： 我们建议确定在没有细胞时引起血管收缩的机制 将血红蛋白引入循环中，作为O2携带血浆的O2载体 通过研究聚乙烯乙二醇（PEG）产生的血管作用来扩展（OCPE） 在该程序中开发了表面装饰的血红蛋白（HBS）。我们将研究压力机 响应各种配方的最高负载，并量化微循环的反应 在仓鼠皮肤模型中，可以在清醒状态下研究而无需麻醉的模型 最多2周的时间。在体内评估的主要微血管参数 是功能性毛细管密度和血管内氧张力分布。测试将分析 关于由于分子血红蛋白而导致的血管活性生成的不同假设 循环，即：1）没有血红蛋白清除； 2）降低血液稀释的粘度， 导致剪切应力降低和内皮放松因子的产生； 3）增加 氧蛋白蛋白的促进扩散和O2自动调节； 4）血红蛋白的程度 通过钉分子屏蔽表面。 OCPE的功效将在条件下确定 等血液稀释和出血性休克。有效的OCPE也必须确保 足够升高的血液粘度，这对于维持足够 微血管功能以及可以用PEG-HBS获得的条件。在血液中 这些分子增加了血浆粘度，导致液压重新分布 循环，降低全身粘度依赖性压力损失并增加周围 反抗。另外，应将这些修饰的血红蛋白的O2解离曲线留下 移动，因此O2释放仅发生在缺氧区域，而不是来自小动脉和组织 充氧是足够的。我们的目标是了解支持血管侵害以支持 OCPE开发优先于毛细管维持微血管功能 灌注对组织生存至关重要，就像充分的氧合一样，通过使用方法 在细胞显微镜水平上的分析，其中血液执行其重要功能。