Attenuating the Oxidative and Myocardial Side-Effects of Acellular Hemoglobin

 描述：基于血红蛋白(Hb)的氧(O2)载体(HBOC)目前正被开发为用于输血医学的红细胞(RBC)替代品。尽管有重大的商业开发，但聚合血红蛋白(PolyHb)溶液(即血液(OPK Biotech，马萨诸塞州剑桥)和Polyheme(诺斯菲尔德实验室公司，伊文斯顿，伊利诺伊州)，一种戊二醛聚合的人Hb)最近的后期临床结果阻碍了进一步的开发。这两种商业产品都在微循环水平上引起血管收缩，并导致全身高血压和氧化组织损伤的发展。这些副作用被认为是通过一氧化氮(NO)清除或氧气(O2)供应过剩机制发生的，并因PolyHb渗入组织间隙而加剧。根据这两种可能的机制，显然，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。因此在这件事上 应用方面，我们假设PolyHb大小将在微循环水平调节血管收缩、全身性高血压和组织氧化损伤。为了验证这一假设，我们计划通过交联剂戊二醛对牛Hb进行交联/聚合，在低O2亲和力状态下合成几种不同大小的PolyHb。为了验证这一应用的中心假设，我们提出了三个具体目标：具体目标1：分析内皮功能在不同大小的PolyHbs氧化组织损伤发展中的作用。具体目标2：分析不同大小多聚血红蛋白存在时的心功能。具体目标3：评估PolyHb在失血性休克复苏后恢复灌流和氧合的能力。这项拟议的工作具有重大意义和创新性，因为它寻求开发用于输血医学的安全和有效的聚Hbs。此外，还将使用最先进的生物物理技术和两个独特的动物模型来了解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.