Attenuating the Oxidative and Myocardial Side-Effects of Acellular Hemoglobin

减轻无细胞血红蛋白的氧化和心肌副作用

• 批准号: 9027128
• 负责人: Pedro Cabrales
• 金额: $ 38.87万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9027128
• 关键词: Accounting; Adverse effects; Affinity; Animal Model; Animals; Antioxidants; Attenuated; Biotechnology; Blood Vessels; Blood Volume; Cardiac; Carrying Capacities; Cattle; Cavia; Cells; Chemistry; Cholesterol; Clinical; Clinical Trials; Deposition; Development; Diffusion; Emerging Communicable Diseases; Endothelial Cells; Erythrocytes; Event; Experimental Animal Model; Extravasation; Formulation; Glutaral; Heme; Hemoglobin; Hemorrhage; Hemorrhagic Shock; Human; Hypertension; Incidence; Infusion procedures; Injury; Intercellular Junctions; Iron; Laboratories; Lead; Light; Lipids; Medicine; Methemoglobin; Myocardial; Myocardial Infarction; Nitric Oxide; Nucleic Acids; Organ; Oxidation-Reduction; Oxidative Stress; Oxygen; Perfusion; Permeability; Phase III Clinical Trials; Physiological; Population; Prevention; Prosthesis; Proteins; Regulation; Resuscitation; Risk; Role; Safety; Signal Transduction; Smooth Muscle Myocytes; Staging; Systemic hypertension; Testing; Tissues; Toxic effect; Transfusion; Translating; Vascular blood supply; Vascular resistance; Work; base; biophysical techniques; crosslink; endothelial dysfunction; feeding; hemodynamics; improved; innovation; molecular size; novel; oxidation; oxidative damage; prevent; public health relevance; response; screening; vasoconstriction

 DESCRIPTION: Hemoglobin (Hb)-based oxygen (O2) carriers (HBOCs) are currently being developed as red blood cell (RBC) substitutes for use in transfusion medicine. Despite significant commercial development, recent late stage clinical results of polymerized hemoglobin (PolyHb) solutions (i.e. Hemopure (OPK Biotech, Cambridge, MA), a glutaraldehyde polymerized bovine Hb; and PolyHeme (Northfield Laboratories Inc., Evanston, IL), a glutaraldehyde polymerized pyridoxylated human Hb) hamper further development. Both of these commercial products elicit vasoconstriction at the microcirculatory level, and lead to the development of systemic hypertension and oxidative tissue damage. These side-effects are hypothesized to occur either by a nitric oxide (NO) scavenging or oxygen (O2) oversupply mechanism and are both exacerbated by PolyHb extravasation into the tissue space. In light of these 2 potential mechanisms, it is apparent that PolyHb size will have a profound impact on the extent of vasoconstriction, systemic hypertension and oxidative tissue toxicity. Therefore in this application, we hypothesize that PolyHb size will regulate vasoconstriction at the microcirculatory level, systemic hypertension and tissue oxidative damage. In order to test this hypothesis, we plan to synthesize several PolyHbs of varying size in the low O2 affinity state by cross-linking/polymerizing bovine Hb using the cross-linking agent glutaraldehyde. In order to test the central hypothesis of this application, we propose 3 specific aims: Specific Aim 1: Analyze the role of endothelial function on the development of oxidative tissue injury to PolyHbs of varying size. Specific Aim 2: Analyze cardiac function in the presence of PolyHbs of varying size. Specific Aim 3: Evaluate the ability of PolyHb to restore perfusion and oxygenation after resuscitation from hemorrhagic shock. The proposed work is both significant and innovative, since it seeks to develop safe and efficacious PolyHbs for use in transfusion medicine. In addition, state-of-the-art biophysical techniques and two unique animal models will be used to understand PolyHb physiological responses and determine the clinical potential of these novel materials.

 描述：目前正在开发基于血红蛋白 (Hb) 的氧 (O2) 载体 (HBOC) 作为红细胞 (RBC) 替代品，用于输血医学。尽管商业化发展显着，但聚合血红蛋白 (PolyHb) 溶液（即 Hemopure（OPK Biotech，剑桥，马萨诸塞州），一种戊二醛聚合牛血红蛋白；和 PolyHeme（Northfield Laboratories Inc.，伊利诺斯州埃文斯顿），一种戊二醛聚合吡啶氧化人血红蛋白）的最新后期临床结果阻碍了进一步的发展。 发展。这两种商业产品都会引起微循环水平的血管收缩，并导致全身性高血压和氧化组织损伤的发生。假设这些副作用是由一氧化氮 (NO) 清除或氧气 (O2) 供应过剩机制引起的，并且都会因 PolyHb 外渗到组织空间而加剧。鉴于这两种潜在机制，很明显，PolyHb 的大小将对血管收缩、全身性高血压和氧化组织毒性的程度产生深远的影响。 因此在这个 应用中，我们假设 PolyHb 大小将调节微循环水平的血管收缩、全身性高血压和组织氧化损伤。为了检验这一假设，我们计划通过使用交联剂戊二醛交联/聚合牛 Hb，合成几种处于低 O2 亲和力状态的不同大小的 PolyHb。为了检验本申请的中心假设，我们提出了 3 个具体目标： 具体目标 1：分析内皮功能对不同大小的 PolyHb 氧化组织损伤发展的作用。具体目标 2：在存在不同大小的 PolyHb 的情况下分析心脏功能。具体目标 3：评估 PolyHb 在失血性休克复苏后恢复灌注和氧合的能力。 拟议的工作既重要又具有创新性，因为它寻求开发用于输血医学的安全有效的 PolyHb。此外，最先进的生物物理技术和两种独特的动物模型将用于了解 PolyHb 生理反应并确定这些新材料的临床潜力。