Cell-Free O2 Carriers: Cerebrovascular Control & Stroke

无细胞氧气载体：脑血管控制

• 批准号: 7046733
• 负责人: RAYMOND Charles KOEHLER
• 金额: $ 36.92万
• 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 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7046733
• 关键词: blood /plasma substitute; blood cell count; blood viscosity; brain circulation; cardiovascular pharmacology; cerebral ischemia /hypoxia; cytochrome P450; endothelin; enzyme activity; gene deletion mutation; heme oxygenase; hemoglobin; hemorrhage; hypotension; infarct; laboratory mouse; laboratory rat; oxygen tension; oxygen transport; prostaglandins; resuscitation; shock; stroke; vasomotion

DESCRIPTION (provided by applicant): Exchange transfusion with cell-free hemoglobin (Hb) permits hematocrit and blood viscosity to be reduced without a proportional decrease in 02 carrying capacity, thereby promoting 02 delivery in hypoperfused states such as stroke and shock. Polymers of Hb appear to be better tolerated in clinical trials than the first generation of cross-linked tetrameric Hb, but there are little data available on the cerebrovascular effects of these commercial polymers. Previously, an Hb polymer without residual cross-linking reagents was developed that does not extravasate or produce hypertension. It normally produces pial arteriolar constriction when viscosity is decreased, and dilation when viscosity is increased, to keep cerebral blood flow (CBF) constant. This pial constriction is mediated by O2-dependent P450 omega-hydroxylase which produces the vasoconstrictor 20-HETE. In addition, two recombinant Hb polymers with different 02 affinities were engineered and unexpectedly indicated that Hb with high 02 affinity was more effective in decreasing infarct volume after stroke. In the present application, the optimal 02 affinity of plasma-based Hb for reducing stroke damage will be determined. Pial arteriolar diameter responses in ischemic border regions will be measured during transfusion to determine 1) if high 02 affinity Hb, which should have less precapillary 02 loss, produces less constriction and better perfusion; 2) if inhibiting omega-hydroxylase activity or administering an endothelin-1 antagonist blocks intraischemic constriction to Hb transfusion, promotes CBF and reduces infarct size; 3) if Hb transfusion produces a delayed upregulation of heme oxygenase (HO) activity that counteracts the initial constriction, and if prior upregulation of HO activity prevents constriction of collateral pial arteries. Both gene deletion and pharmacological procedures will be used. Because of the interest in using Hb solutions in hemorrhagic shock, the effect of resuscitation with a large Hb polymer on the peripheral and cerebral circulation will be investigated. Inhibition of omega-hydroxylase will be tested as a strategy to promote cerebral vasodilation after resuscitation from shock. Therefore, this proposal will provide new mechanistic insights into how cell-free Hb polymers can be used to promote 02 delivery during stroke and shock.

描述（由申请人提供）：与无细胞血红蛋白（HB）的交换输血允许血细胞比容和血液粘度在不成比例下降的情况下降低02携带能力，从而促进诸如中风和冲击等催眠状态的02递送。与第一代交联的四聚体HB相比，HB的聚合物在临床试验中的耐受性似乎更好，但是关于这些商业聚合物的脑血管效应的数据很少。以前，开发了没有剩余的交联试剂的HB聚合物，不会外出或产生高血压。当粘度降低时，它通常会产生伴随的动脉收缩，并在粘度增加时扩张，以保持脑血流（CBF）恒定。这种伴侣的收缩是由O2依赖性的P450欧米茄羟化酶介导的，该欧米茄氧化酶产生血管收缩20-HETE。此外，设计了两种具有不同02亲和力的重组HB聚合物，并出乎意料地表明，具有高02亲和力的HB在中风后减少梗塞体积更有效。在本应用中，将确定基于等离子体的Hb减少中风损伤的最佳02亲和力。在输血期间，将测量缺血边界区域中的小动脉直径反应，以确定1）如果高02亲和力Hb（应该较少的毛细血管前02损耗）会产生较少的收缩和更好的灌注； 2）如果抑制欧米茄 - 羟化酶活性或施用内皮素-1拮抗剂会阻止术内收缩到HB输血，促进CBF并降低梗塞大小； 3）如果HB输血会产生延迟的上调血红素氧酶（HO）活性，以抵消初始收缩，并且如果事先上调HO活性会阻止侧支pial动脉的收缩。将使用基因缺失和药理程序。由于有兴趣在出血性休克中使用HB溶液，因此将研究使用大HB聚合物对周围和脑循环的复苏作用。将测试欧米茄羟化酶的抑制作用将作为一种促进休克复苏后脑血管舒张的策略。因此，该提案将提供新的机械见解，以了解如何使用无细胞的HB聚合物在中风和冲击过程中促进02递送。