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.

项目摘要 输血介绍的理论受益的理论受益于血氧的承载能力与 氧递送。但是，我们的临床前和临床研究表明，储存的血液失去了其氧合的能力 组织。输血后可能发生的后遗症（肾脏损伤，心肌梗塞，死亡）是一致的 有一种想法，即养血可能会加剧而不是纠正贫血诱发的缺氧。 我们发现，储存的血液显着降低了一氧化氮/s-硝基硫醇（no/sno） 生物活性包括血红蛋白（SNO-HB）的S-亚硝基化形式，这是血流的主要介体和 外围氧递送。 SNO的这种下降为血管舒张受损提供了机械基础 储存的红细胞（RBC）的活性以及为什么输血甚至少量血液的解释 可能会损害组织灌注。我们通过证明SNO-HB的恢复来建立在这一小说中的发现 级别（果糖基化）纠正了储存诱导的RBC氧和输血诱导的缺陷 多种临床前输血范式中的器官功能障碍，我们已经开始临床研究以评估 输血对组织氧合的影响。我们还开发了一流的果糖基化剂 已经进行了临床测试。 我们的定位是提供有关输血对人类组织氧合作用的急需数据 并通过以下目的提高果糖基化疗法对氧气递送的好处： 1。进一步了解RBC导出SNO生物活性的分子机制 调节组织氧合； 2。开发一种用于受控的体内肾上腺素化的装置； 3。确定果皮化是否可以改善小儿旁路动物模型的手术后结局； 和 4。在人类中进行自体输血研究，以确定肾上腺化的益处 组织氧合。 总体而言，我们的研究应提供急需的洞察力，以了解输血对组织氧合的影响， 阐明与输血相关的不良缺血事件的机械基础，并加速 治疗方法的开发（SNO-HB的补充）。恢复氧气输送能力 养血的血液应导致输血实现其临床目的：血管舒张 微循环以改善麻醉患者的最终器官氧递送。在世界上的 银行RBC的供应缺乏SNO-HB，肾上腺素化可能具有巨大的治疗承诺。