Attenuating the Oxidative and Myocardial Toxicity of Polymerized Hemoglobins

基于血红蛋白（Hb）的氧（O2）载体（HBOCs）目前正在开发作为红细胞（RBC）的替代品，用于输血医学。尽管有重大的商业发展，但最近的后期临床结果显示，聚合血红蛋白（PolyHb）溶液(即Hemopure®（OPK Biotech, Cambridge， MA）是一种戊二醛聚合的牛血红蛋白；PolyHeme (Northfield Laboratories Inc., Evanston， IL)，一种戊二醛聚合吡啶羟化人血红蛋白)阻碍了进一步的发展。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性组织损伤的发展。这些副作用被认为是由一氧化氮（NO）清除或氧（O2）供过于求的机制引起的，并且都因PolyHb外渗到组织空间而加剧。鉴于这两种潜在的机制，PolyHb的大小显然会对血管收缩的程度、全身性高血压和氧化组织毒性产生深远的影响。因为，增加HBOC的大小会阻止其通过内皮细胞-细胞连接的外渗，降低HBOC扩散系数的大小，从而降低NO清除的程度和血管壁的高氧合。通过这种简单的方法，我们的团队证明了增加PolyHb的分子大小可以消除两种不同动物的血管收缩和高血压。防止HBOC外渗还应通过防止HBOC与组织密切接触来减少ros诱导的组织氧化损伤。因此，在本应用中，我们假设HBOC的大小会调节组织和器官的氧化损伤以及心肌功能。为了验证这一应用的中心假设，我们提出了两个具体目标：具体目标1：分析内皮功能对PolyHb毒性动力学的作用。专项目的2：分析PolyHb在心肌功能中的作用。拟议的工作既重要又创新，因为它寻求开发安全有效的PolyHbs用于输血医学。此外，将使用最先进的生物物理技术和两种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. Since, increasing the size of the HBOC will prevent its extravasation through endothelial cell-cell junctions, decreasing the magnitude of the HBOC diffusion coefficient and thus decreasing both the extent of NO scavenging and hyper-oxygenation of the blood vessel wall. Using this simple approach, our team demonstrated that increasing the molecular size of PolyHb eliminated vasoconstriction and hypertension in two different animal species. Prevention of HBOC extravasation should also decrease ROS-induced tissue oxidative damage by preventing the HBOC from coming into intimate contact with tissues. Therefore in this application, we hypothesize that HBOC size will regulate oxidative damage to tissues and organs as well as myocardial function. In order to test the central hypothesis of this application, we propose 2 specific aims: Specific Aim 1: Analyze the role of endothelial function on PolyHb toxicokinetics. Specific Aim 2: Analyze the role of PolyHb on myocardial function. 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.