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

基本信息

批准号：
8122380
负责人：
JONATHAN S. STAMLER
金额：
$ 39.25万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-16 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8122380
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

项目摘要

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）输注是用于维持和/或改善组织和终末器官氧输送的最常见的治疗干预措施。尽管这种治疗的概念很简单，但最近的研究表明，同种异体红细胞输注通常不会产生什么临床益处，实际上可能会伤害接受者。我们最近确定，人类血液的储存会导致一氧化氮 (NO) 生物活性（S-亚硝基血红蛋白）的快速损失，而这与储存的红细胞扩张血管从而输送氧气的能力的损失恰恰是平行的。我们进一步表明，通过补充 NO 生物活性，缺陷得到纠正。我们现在还发现，长期储存会导致 S-亚硝基血红蛋白的再生缺陷（即较旧的血液明显），这种缺陷至少部分是可逆的。这种储存血液中生理活性丧失的新机制，以及更重要的是，对其纠正的假定干预措施，提出了在施用浓缩红细胞之前恢复 NO 生物活性可能显着改善输血相关缺血发病率的可能性。我们的研究结果导致了目前的拨款申请，我们将在其中测试以下假设：再亚硝基化以增加S-亚硝基血红蛋白含量，恢复储存红细胞的缺氧血管舒张活性，从而改善输血期间的组织氧输送和生理状态。研究目标： 1. 优化和验证大规模再亚硝基化的体外方法，以恢复库存红细胞的缺氧血管舒张活性，与血型和储存条件无关；和 2. 进行有针对性的体内评估，以证明输血前再亚硝基化对血流和局部氧输送的益处。通过本文详细介绍的拟议的一系列台式、临床前和临床实验，我们将建立大规模的方法来重新亚硝基化储存的血液并彻底评估其生理益处。我们预计这些研究产生的信息可能会影响临床护理的根本变化。恢复储存红细胞的一氧化氮生物活性和供氧能力将使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终末器官供氧。再亚硝基化将是一种新型的治疗干预措施，非常容易实施，可以产生显着的临床效益和经济节约。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 万单位浓缩红细胞 (RBC)，以治疗各种急性原因和慢性疾病引起的贫血。然而，现在人们认识到，注射浓缩红细胞不仅不能改善氧气输送，反而可能加剧缺血。基于红细胞血管舒张能力受损（由储存相关的一氧化氮生物活性消耗引起）在很大程度上导致输血相关发病率的主张，我们建议制定在临床环境中恢复红细胞一氧化氮生物活性的方法，并确定恢复红细胞血管舒张是否可以减轻输血的有害影响。