Cell Free O2 Carriers: Cerebrovascular Control and Stroke

无细胞氧气载体：脑血管控制和中风

• 批准号: 8114472
• 负责人: RAYMOND Charles KOEHLER
• 金额: $ 8.2万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8114472
• 关键词: Acute; Adverse effects; Animals; Antioxidants; Arteries; Behavior; Biochemical; Blood Vessels; Blood capillaries; Blood flow; Brain; Cattle; Cause of Death; Cells; Cerebrovascular Circulation; Clinical; Coagulation Process; Data; Disease; Distal; Dose; Endothelin; Endothelium; Engineering; Enzymes; Erythrocytes; Experimental Models; Extravasation; Female; Filament; Gender; Generations; Goals; Hematocrit procedure; Hemoglobin; Infarction; Infusion procedures; Injury; Investigation; Ischemia; Ischemic Stroke; Knowledge; Link; Liquid substance; Membrane; Middle Cerebral Artery Occlusion; Modeling; Molecular Weight; Mus; Nitric Oxide; Nitric Oxide Synthase; Nitrite Reductase; Nitrites; Outcome; Oxidants; Oxidative Stress; Oxygen; Perfusion; Peripheral; Pharmaceutical Preparations; Plasma; Polyethylene Glycols; Polymers; Production; Property; Protocols documentation; Rattus; Recombinants; Recycling; Reticuloendothelial System; Role; Societies; Sodium Nitrite; Solutions; Stroke; Sulfhydryl Compounds; Superoxides; Surface; Survivors; Testing; Therapeutic; Tissues; Transfusion; Translating; Translations; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; Viscosity; Work; arginase; arteriole; base; capillary; catalase; cerebrovascular; crosslink; design; disability; feeding; improved; inhibitor/antagonist; injured; male; mimetics; molecular size; mortality; neurobehavior; next generation; novel; oxidant stress; polymerization; pressure; public health relevance; scale up; shear stress; vascular bed; vasoconstriction

DESCRIPTION (provided by applicant): The goal of this project is increase tissue rescue from stroke by improving O2 delivery with the use of cell- free hemoglobin (Hb) O2 carriers (HBOC) and agents that simultaneously improve collateral blood flow. An early clinical attempt to use the first generation of crosslinked tetrameric Hb was not successful partially because of unwanted side effects related to scavenging of the vasodilator, nitric oxide (NO), and production of the vasoconstrictor, endothelin. Our previous work demonstrated that polymerization of Hb avoided some of these side effects and rescued tissue from stroke in animals. However, dilation of pial arteries in the distal ischemic territory adjacent to anastomotic vessels was not sustained, perfusion was not improved, and tissue rescue was likely submaximal. Preliminary data indicated that dilation of these arteries could be better sustained during prolonged ischemia by co-administration of an inhibitor of arginase, an enzyme that can constrain endothelial NO production and promote superoxide generation by uncoupled NO synthase, or by co-administration of nitrite, which enables the NO scavenged by Hb to be recycled by virtue of the nitrite reductase activity of Hb. Moreover, Hb decorated with polyethylene glycol (PEG-Hb) may be superior to previously tested polymerized Hb because of its higher oncotic pressure and viscosity, which promotes endothelial shear stress-induced NO production. Indeed, transfusion of PEG-Hb during early transient focal ischemia was found to markedly reduce cortical infarct volume by 83%. Moreover, polynitroxylation of PEG- Hb, which confers antioxidant properties and limits formation of highly reactive ferryl Hb, was found to improve intraischemic dilation of pial arteries and to rescue cortex by 89%. Aim 1 of this proposal is to optimize the transfusion protocol and dose of PEG-Hb and polynitroxylated PEG-Hb and determine if polynitroxylation provides added benefit in a more severe model of transient ischemia and in an embolic clot model. Aim 2 is to better understand the role of arginase activity in the progressive loss of vasodilation in the ischemic border region. This aim will reveal if an arginase inhibitor reduces endothelial oxidative stress and if co-administration with the HBOC that was optimal in Aim 1 provides additional vasodilation, improved blood flow, and tissue rescue. Aim 3 is to determine if co-administration of nitrite with an HBOC also provides additional vasodilation and tissue rescue. Using the most efficacious vasodilating agents, HBOC product, and transfusion protocol seen in Aims 1-3, the therapeutic window of opportunity, long-term outcome and gender effects will be investigated in an embolic clot model of stroke in Aim 4. Therefore, this proposal will capitalize on more recent advances in our knowledge of the properties of HBOC and vascular control mechanisms to optimize O2 delivery and maximize tissue rescue from ischemic stroke. Results from these studies have the potential to be translated into clinical therapy for the acute treatment of stroke, a disease with high mortality and devastating disabilities that represent a large burden on society. PUBLIC HEALTH RELEVANCE: Stroke is the third leading cause of death, and the disabilities that remain in survivors place a major burden on society. In experimental models of stroke, we will investigate the use of chemically modified hemoglobin molecules, which are endowed with unique physical and antioxidant properties, as transfusion fluids that enable more oxygen to be delivered to the injured brain without adding to the oxidant stress of the stroke. We will also investigate drugs that can dilate arteries and permit more blood flow and oxygen to be delivered selectively to the injured brain when administered together with the hemoglobin solution and thereby enhance rescue of tissue from ischemic stroke.

描述（由申请人提供）：该项目的目的是通过使用无细胞 - 无细胞 - HB）O2载体（HBOC）（HBOC）和同时改善附加血流的药物来增加中风的组织救援。早期使用第一代交联四聚体HB的临床尝试并未成功，因为与清除血管舒张剂，一氧化氮（NO）和血管收缩剂Endophelin的产生有关的不必要的副作用。我们以前的工作表明，HB的聚合避免了其中一些副作用，并从动物的中风中救出了组织。然而，在与吻合血管相邻的远端缺血区域中的河向动脉扩张没有持续，灌注没有得到改善，并且组织营救可能是次最大的。初步数据表明，在长期缺血期间可以通过共同给药精氨酸酶的抑制剂可以更好地维持这些动脉的扩张，而精氨酸酶的抑制剂可以限制不合偶联的酶，或通过未偶联的合成酶来限制内皮的无氧化物的产生，或者通过no nose no noceed of no noceed of noceed of heb shabe for habe deyceed hbb havenge nb hab shbeed hab shbe deyceed hbbeced hbbeed hb nb hbb n abe hb n abe hb n abe n beceed hbbeed hab s not of hb hb。 Hb的亚硝酸盐还原酶活性。此外，由于其较高的肿瘤压力和粘度，用聚乙烯甘油（PEG-HB）装饰的HB可能优于先前测试的聚合Hb，从而促进了内皮剪切应力引起的无产生。实际上，发现早期短暂性局灶性缺血期间PEG-HB的输血显着将皮质梗塞量降低了83％。此外，发现PEG-HB的多硝基化既赋予了抗氧化特性，并限制了高反应性渡轮Hb的形成，可改善伴培养基动脉的术内扩张，并挽救皮层的抗氧化特性，并升高89％。该提案的目标1是优化PEG-HB和多硝基化PEG-HB的输血方案和剂量，并确定多硝基氧基化是否在更严重的瞬态缺血模型和栓塞凝块模型中提供了额外的好处。目的2是更好地了解精氨酸活性在缺血边界区域进行性血管舒张的作用。该目标将揭示精氨酸酶抑制剂是否减少了内皮氧化应激，并且是否与AIM 1中最佳的HBOC共同给药是否提供了额外的血管舒张，改善的血液流动和组织救援。 AIM 3是确定亚硝酸盐与HBOC的共同给药是否还提供了其他血管舒张和组织救援。使用目标1-3中看到的最有效的血管扩张剂，HBOC产品和输血方案，将在AIM 4中的栓塞凝块模型中进行治疗范围，长期结局和性别效应。 中风。这些研究的结果有可能转化为中风急性治疗的临床治疗，这种疾病具有高死亡率和毁灭性残疾的疾病，代表了社会的巨大负担。 公共卫生相关性：中风是死亡的第三大主要原因，而残障人士仍然留在幸存者身上，给社会带来了重大负担。在中风的实验模型中，我们将研究化学改良的血红蛋白分子的使用，这些分子具有独特的物理和抗氧化特性，作为输血液，可以使更多的氧气递送到受伤的脑，而无需添加中风的氧化应力。我们还将研究可以扩张动脉的药物，并允许与血红蛋白溶液一起施用时，可以选择地将更多的血流和氧气递送到受伤的大脑中，从而增强缺血性中风的组织救助。