Attenuating the Oxidative and Myocardial Side-Effects of Acellular Hemoglobin

 产品说明： 目前正在开发基于血红蛋白（Hb）的氧（O2）载体（HBOC），作为输血医学中使用的红细胞（RBC）替代品。尽管有显著的商业开发，聚合血红蛋白（PolyHb）溶液（即Hemopure Hb（OPK Biotech，剑桥，MA），一种戊二醛聚合的牛Hb;和PolyHeme Hb（Northfield Laboratories Inc.，Evanston，IL），戊二醛聚合的吡啶氧基化的人Hb）阻碍进一步发育。这两种商业产品都在微循环水平引起血管收缩，并导致全身性高血压和氧化性组织损伤的发展。这些副作用被假设为通过一氧化氮（NO）清除或氧气（O2）过度供应机制发生，并且都因PolyHb外渗到组织间隙中而加剧。根据这两种潜在机制，很明显，PolyHb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影响。 因此，在这 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，我们计划合成几个不同大小的聚血红蛋白在低O2亲和力状态下的交联/聚合牛血红蛋白使用交联剂戊二醛。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PolyHb的氧化组织损伤发展的作用。具体目标2：在不同大小的PolyHb存在下分析心脏功能。具体目标3：评价PolyHb在失血性休克复苏后恢复灌注和氧合的能力。 拟议的工作既有意义又有创新性，因为它旨在开发安全有效的PolyHbs用于输血医学。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的生理反应，并确定这些新材料的临床潜力。

 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.