Restoration and Function of S-Nitrosothiol in Stored Blood

储存血液中S-亚硝基硫醇的恢复和作用

• 批准号: 9282793
• 负责人: JONATHAN S. STAMLER
• 金额: $ 54.94万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9282793
• 关键词: Advanced Development; Adverse event; Anemia; Animals; Autologous; Blood; Blood Banks; Blood Transfusion; Blood flow; Breathing; Carrying Capacities; Cessation of life; Clinical; Clinical Chemistry; Clinical Research; Data; Devices; Environmental air flow; Erythrocytes; Event; Functional disorder; Goals; Hemoglobin; Hemorrhage; Human; Hypoxia; Impairment; Injury; Ischemia; Kidney; Life; Light; Measures; Mediating; Mediator of activation protein; Methods; Microcirculation; Modeling; Molecular; Mus; Mutant Strains Mice; Myocardial Infarction; Nitric Oxide; Organ; Oxygen; Patients; Perfusion; Peripheral; Physiological; Positioning Attribute; Protocols documentation; Public Health; Role; Route; S-Nitrosothiols; SKIL gene; Science; Sheep; Signal Transduction; System; Testing; Therapeutic; Time; Tissues; Transfusion; Translating; Trauma; Vasodilation; Wild Type Mouse; adverse outcome; base; design; effective therapy; ethyl nitrite; healthy volunteer; human tissue; improved; in vivo; insight; mutant; novel; pre-clinical; prognostic; public health relevance; research clinical testing; response; restoration; therapeutic development; tissue oxygenation

PROJECT SUMMARY The therapeutic benefit of transfusion presumes a direct correlation between blood oxygen carrying capacity and oxygen delivery. However, studies have shown that stored blood loses its ability to oxygenate tissues. The sequelae that can occur after transfusion (renal injury, myocardial infarction, death) are consistent with the idea that banked blood may exacerbate rather than correct anemia-induced hypoxia. We have discovered that banked blood has markedly diminished levels of nitric oxide/S-nitrosothiol (NO/SNO) bioactivity including reduced amounts of the S-nitrosylated form of hemoglobin (SNO-Hb), a major mediator of blood flow and peripheral oxygen delivery. This decline in SNO provides a mechanistic basis for the impaired vasodilatory activity of stored red blood cells (RBCs) and an explanation for why transfusion of even small amounts of blood may impair tissue perfusion. We have built on this novel finding by demonstrating that restoration of SNO-Hb levels (renitrosylation) corrects storage-induced deficiencies in RBC oxygen delivery and transfusion-induced organ dysfunction in multiple preclinical transfusion paradigms, and we have initiated clinical studies to assess the effects of transfusion on human tissue oxygenation. We have also developed first-in-class renitrosylating agents that are already undergoing clinical testing. We are positioned to provide critically needed data on the effects of transfusion on tissue oxygenation in humans and to advance the benefits of renitrosylation therapy on oxygen delivery through the following aims: 1. To advance understanding of the molecular mechanisms by which RBCs deploy SNO-based signals to regulate tissue oxygenation in fresh and stored blood. 2. To develop a device for ex vivo renitrosylation. 3. To determine if the physiologic responses to transfusion with renitrosylated RBCs are superior to untreated banked blood in a preclinical trauma model. 4. To conduct an autologous standard flow (i.e. non-trauma) transfusion study in humans with and without renitrosylation to delineate the physiologic effects of transfusion and the benefits of increased/restored SNO-Hb levels on tissue oxygenation. Collectively, our studies will provide much-needed insight into the effects of transfusion on tissue oxygenation, shed light on the mechanistic basis of adverse ischemic events associated with transfusion, and accelerate development of therapeutic approaches (repletion of SNO-Hb). Restoration of the oxygen delivery capabilities of banked blood should result in blood transfusion achieving its clinical purpose: vasodilation in the microcirculation to improve end-organ oxygen delivery in the anemic patient. To the extent that the world's supplies of banked RBCs are deficient in SNO-Hb, renitrosylation may hold significant therapeutic promise.

项目概要 输血的治疗效果假定与血液携氧能力直接相关 和氧气输送。然而，研究表明储存的血液失去了为组织供氧的能力。这 输血后可能出现的后遗症（肾损伤、心肌梗塞、死亡）与这个想法一致 储存的血液可能会加剧而不是纠正贫血引起的缺氧。 我们发现储存的血液中一氧化氮/S-亚硝基硫醇 (NO/SNO) 的水平显着降低 生物活性，包括减少 S-亚硝基化形式的血红蛋白 (SNO-Hb) 的量，SNO-Hb 是 血流量和外周氧输送。 SNO 的下降为受损的机制提供了基础 储存的红细胞 (RBC) 的血管舒张活性以及为何输注少量红细胞的解释 大量的血液可能会损害组织灌注。我们在这一新颖发现的基础上证明了 恢复 SNO-Hb 水平（再亚硝基化）可纠正储存引起的红细胞氧输送缺陷 以及多种临床前输血范例中输血引起的器官功能障碍，我们已经启动 评估输血对人体组织氧合影响的临床研究。我们还开发了 一流的再亚硝基化剂已正在进行临床测试。 我们的定位是提供关于输血对组织氧合影响的急需数据。 人类并通过以下目标提高再亚硝基化疗法对氧气输送的益处： 1. 加深对 RBC 部署基于 SNO 的信号的分子机制的理解 调节新鲜和储存血液中的组织氧合。 2. 开发离体再亚硝基化装置。 3. 确定输注重亚硝基化红细胞的生理反应是否优于输注 临床前创伤模型中未经处理的储存血液。 4. 对患有或不患有以下疾病的人类进行自体标准流量（即非创伤）输血研究 再亚硝基化来描述输血的生理效应以及增加/恢复的益处 SNO-Hb 水平对组织氧合的影响。 总的来说，我们的研究将为输血对组织氧合的影响提供急需的见解， 阐明与输血相关的不良缺血事件的机制基础，并加速 治疗方法的开发（补充 SNO-Hb）。恢复供氧能力 储存的血液应该导致输血达到其临床目的：血管舒张 改善贫血患者终末器官氧输送的微循环。就世界范围内而言 由于储存的红细胞供应缺乏 SNO-Hb，因此再亚硝基化可能具有重要的治疗前景。