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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结