Restoration and Function of S-nitrosothiol in Stored Blood

储存血液中S-亚硝基硫醇的恢复及作用

• 批准号: 8294535
• 负责人: JONATHAN S. STAMLER
• 金额: $ 33.73万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-16 至 2014-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8294535
• 关键词: Abbreviations; Accounting; Acute; Adenosine Triphosphate; Affect; Affinity; Allogenic; American; Anemia; Applications Grants; Biological Availability; Blood; Blood Banks; Blood Circulation; Blood Transfusion; Blood Vessels; Blood flow; Blood typing procedure; Bypass; Caliber; Carrying Capacities; Chronic Disease; Clinical; Collection; Coupled; Defect; Economics; Erythrocyte Transfusion; Erythrocytes; Expenditure; Failure; Forearm; Hemoglobin; Homeostasis; Human; Hypoxia; Impairment; In Vitro; Infusion procedures; International System of Units; Intervention; Ischemia; Leukocytes; Life; Lung; Medical; Mercury; Metabolic; Methodology; Methods; Modification; Morbidity - disease rate; Natural regeneration; Nitric Oxide; Nitric Oxide Synthase; Organ; Oxygen; Patients; Perfusion; Phosphate Buffer; Physiological; Procedures; Public Health; Radial; Research; Rheology; Role; S-Nitrosothiols; S-nitrosohemoglobin; SKIL gene; Saline; Savings; Series; Signal Transduction; Testing; Text; Therapeutic Intervention; Time; Tissues; Transducers; Transfusion; Vasodilation; base; blood group; clinical care; cost; ethyl nitrite; human NOS3 protein; improved; in vivo; novel; novel therapeutic intervention; photolysis; pre-clinical; pressure; prevent; public health relevance; research study; response; restoration; sensor; tissue oxygenation; vasoconstriction

DESCRIPTION (provided by applicant): Red blood cell (RBC) transfusion is the most common therapeutic intervention employed to maintain and/or improve tissue and end-organ oxygen delivery. Despite the conceptual simplicity of this treatment recent studies indicate that allogenic RBC infusion often produces little clinical benefit and may actually harm the recipient. We recently determined that storage of human blood leads to rapid losses in nitric oxide (NO) bioactivity (S-nitroso-hemoglobin) that are precisely paralleled by losses in the ability of stored RBCs to dilate blood vessels and thereby deliver oxygen. We further showed that by replenishing NO bioactivity, the defect was corrected. We have now also found that prolonged storage leads to a defect in the regeneration of S-nitroso-hemoglobion (i.e. evident with older blood), which is at least partly reversible. This novel mechanism for the loss of physiological activity in banked blood and, more importantly, a putative intervention for its correction, raise the possibility that restoration of NO bioactivity prior to administration of packed RBCs may significantly ameliorate transfusion-associated ischemic morbidity. Our findings have led to the present grant application in which we will test the following hypothesis: Renitrosylation to increase S-nitroso-hemoglobin content restores the hypoxic-vasodilatory activity of stored RBCs to improve tissue oxygen delivery and physiologic status during transfusion. Research Objectives: 1. To optimize and validate in vitro methods of large-scale renitrosylation that restore hypoxic- vasodliatory activity to banked RBCs independent of blood group and across storage conditions; and 2. To conduct focused in vivo assessments to demonstrate the benefits of pre-transfusion renitrosylation on blood flow and local oxygen delivery. Through the proposed series of bench top, pre-clinical, and clinical experiments detailed herein, we will establish large-scale methodology to renitrosylate stored blood and thoroughly assess the physiological benefits. We anticipate that the information generated from these studies may affect fundamental changes in clinical care. Restoration of NO bioactivity and oxygen delivery capabilities of stored RBCs will result in blood transfusion achieving its clinical purpose: vasodilation in the micro-circulation to maintain or enhance end- organ oxygen delivery in the anemic patient. Renitrosylation would be a novel therapeutic intervention, extremely easy to implement, that could yield significant clinical benefits and economic savings. PUBLIC HEALTH RELEVANCE: Blood transfusion is among the most commonly performed medical procedures: each year approximately 5 million Americans receive 14 million units of packed red blood cells (RBCs) to treat anemia resulting from a variety of acute causes and chronic disease states. However, it is now recognized that the administration of packed RBCs may not only fail to improve oxygen delivery but may actually worsen ischemia. Based on the proposition that an impairment in the vasodilatory ability of RBCs (resulting from storage-related depletion of nitric oxide bioactivity) contributes substantially to transfusion-related morbidity, we propose to generate methods for the restoration of RBC nitric oxide bioactivity in clinical settings, and to determine whether restoration of RBC vasodilation ameliorates the deleterious effects of transfusion.

描述（由申请人提供）： 红细胞（RBC）输血是用于维持和/或改善组织和末端器官氧递送的最常见治疗干预措施。尽管这项治疗的概念很简单，最近的研究表明，同种异体RBC输注通常几乎没有临床益处，实际上可能会损害接受者。我们最近确定，人血的储存会导致一氧化氮（NO）生物活性（S-硝基 - 血红蛋白）的迅速损失，这些氧化物（S-硝基 - 血红蛋白）与储存的RBC扩张血管的能力的损失完全平行，从而散布了氧气。我们进一步表明，通过不补充任何生物活性，纠正了缺陷。现在，我们还发现，长时间的存储会导致S-硝基 - 毛细血管再生的缺陷（即显而易见的血液），这至少是部分可逆的。这种新型的机制是在储存的血液中丧失生理活性的机制，更重要的是，对其进行纠正的推定干预措施提高了在填充RBC之前恢复无生物活性的可能性，可能会显着改善输血相关的缺血性发病率。我们的发现导致了当前的赠款应用，在该应用中，我们将测试以下假设：肾上腺素化以增加S-硝基 - 血红蛋白含量恢复储存的RBC的低氧溶解活性，以改善输血期间的组织氧和生理状态。 研究目标： 1。优化和验证大规模肾上腺素化的体外方法，以将低氧 - 血管造期活性恢复到独立于血液组和跨储存条件的库RBC中；和 2。进行重点在体内评估中，以证明再灌注春糖基化对血流和局部氧递送的好处。 通过拟议的一系列台式台面，临床前和临床实验，我们将建立大规模的方法，以列硝基苯甲酸酯储存的血液并彻底评估生理益处。我们预计从这些研究产生的信息可能会影响临床护理的根本变化。恢复未恢复的RBC的生物活性和氧递送能力将导致输血实现其临床目的：微循环中的血管舒张以维持或增强贫血患者的末端器官氧的递送。 果糖基化将是一种新型的治疗干预措施，非常容易实施，可以产生可观的临床益处和经济节省。 公共卫生相关性： 输血是最常见的医疗程序之一：每年约有500万美国人接受1400万单位的填充红细胞（RBC）来治疗各种急性原因和慢性疾病状态的贫血。但是，现在已经认识到，装满RBC的给药不仅可能无法改善氧气递送，而且实际上可能会使缺血恶化。基于这样的主张，即RBC的血管舒张能力受损（由储存相关的一氧化氮氧化物的耗尽引起的损害）显着促进与输血相关的发病率，我们建议生成用于恢复RBC氧化物氧化物在临床环境中的恢复和RBC的恢复RBC的方法的方法。输血。