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: 10586343
• 负责人: JONATHAN S. STAMLER
• 金额: $ 56.72万
• 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: 2016-12-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586343
• 关键词: Acceleration; Adverse event; Anemia; Animal Model; Animals; Autologous; Automobile Driving; Binding; Blood; Blood Banks; Blood Transfusion; Blood Vessels; Blood flow; Bypass; COVID-19 pandemic; Cardiovascular Physiology; Carrying Capacities; Cessation of life; Childhood; Clinical; Clinical Research; Clinical Trials; Control Animal; Data; Devices; Erythrocytes; Event; Functional disorder; Genetic; Goals; Heart Injuries; Heart failure; Hemoglobin; Hemoglobin concentration result; Homeostasis; Human; Hypoxia; Impairment; Inhalation; Injury to Kidney; Ischemia; Life; Measures; Mediating; Mediator; Medical; Methods; Microcirculation; Molecular; Mus; Mutant Strains Mice; Mutate; Myocardial Infarction; Myocardial Ischemia; Nitric Oxide; Observational Study; Operative Surgical Procedures; Organ; Outcome; Oxygen; Pathology; Patient-Focused Outcomes; Patients; Perfusion; Peripheral; Personal Satisfaction; Physiological; Positioning Attribute; Postoperative Period; Procedures; Protocols documentation; Public Health; Pulmonary Heart Disease; Pulmonary Hypertension; Regulation; Role; S-Nitrosothiols; SKIL gene; Site; Skeletal Muscle; System; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Transfusion; Vasodilation; adverse outcome; constriction; design; effective therapy; healthy volunteer; improved; improved outcome; in vivo; insight; novel; organ injury; pharmacologic; pre-clinical; preclinical study; prognostic; public health relevance; research clinical testing; response; restoration; sensor; therapeutic development; tissue biomarkers; tissue oxygenation

PROJECT SUMMARY The therapeutic benefit of transfusion presumes a direct correlation between blood oxygen carrying capacity and oxygen delivery. However, our preclinical and clinical studies show 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 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 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 further advance understanding of the molecular mechanisms by which RBCs export SNO bioactivity to regulate tissue oxygenation; 2. To develop a device for controlled ex vivo renitrosylation; 3. To determine if renitrosylation can improve post-surgical outcome in an animal model of pediatric bypass; and 4. To conduct an autologous transfusion study in humans to determine the benefits of renitrosylation on tissue oxygenation. Collectively, our studies should 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血液携氧能力与血氧浓度之间存在直接相关性。 然而，我们的临床前和临床研究表明，储存的血液失去了充氧能力。 输血后可能出现的后遗症（肾损伤、心肌梗塞、死亡）是一致的。 认为储存的血液可能会恶化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 S-亚硝基化形式的血红蛋白 (SNO-Hb)，它是血流和血流的主要介质 SNO 的下降为血管舒张功能受损提供了机制基础。 储存的红细胞 (RBC) 的活性以及为什么要输血（即使是少量）的解释 可能会损害组织灌注 我们在这一新发现的基础上证明了 SNO-Hb 的恢复。 水平（再亚硝基化）可纠正储存引起的红细胞氧输送和输血引起的缺陷 多种临床前输血范例中的器官功能障碍，我们已经启动了临床研究来评估 我们还开发了一流的再亚硝基化剂。 已经在进行临床测试。 我们的定位是提供关于输血对人体组织氧合影响的急需数据 并通过以下目标提高再亚硝基化疗法对氧输送的益处： 1. 进一步加深对红细胞输出SNO生物活性的分子机制的理解 调节组织氧合； 2. 开发可控离体再亚硝基化装置； 3. 确定再亚硝基化是否可以改善儿科搭桥动物模型的术后结果； 和 4. 在人体中进行自体输血研究，以确定再亚硝基化对人类的益处 组织氧合。 总的来说，我们的研究应该提供急需的关于输血对组织氧合的影响的见解， 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）。 储存的血液应该导致输血达到其临床目的：血管舒张 微循环改善贫血患者的终末器官氧输送 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。