Storage Lesion in Banked Blood Due to Disruption of Nitric Oxide Homeostasis

由于一氧化氮稳态破坏导致储存血液中的储存损伤

• 批准号: 8901566
• 负责人: Mark T Gladwin
• 金额: $ 4.96万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-18 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8901566
• 关键词: Acetylcholine; Acute; Adhesives; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Autologous; Binding; Biochemical; Biological Availability; Blood; Blood Banks; Blood Platelets; Blood Transfusion; Blood Vessels; Blood flow; Canis familiaris; Cell Communication; Cells; Chronic Disease; Clinical; Collaborations; Computer Simulation; Critical Illness; Data; Development; Electron Spin Resonance Spectroscopy; Endothelial Cells; Endothelium; Erythrocyte Transfusion; Erythrocytes; FDA approved; Foundations; Functional disorder; Funding; Goals; Health; Hemoglobin; Hemolysis; Homeostasis; Human; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Iron; Isotope Labeling; Isotopes; Laboratories; Length; Lesion; Measures; Mediating; Metabolism; Methodology; Mitochondria; Modeling; Molecular Biology; Mus; Myography; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitrites; Nitrogen; Operative Surgical Procedures; Organ; Outcome; Pathway interactions; Patients; Platelet Activation; Pneumonia; Preparation; Procedures; Prodrugs; Production; Protocols documentation; Publications; Reactive Oxygen Species; Request for Applications; Risk; Role; Safety; Severities; Signal Transduction; Signaling Molecule; Staphylococcus aureus; Stream; System; Systemic infection; Testing; Therapeutic; Time; Transfusion; Translations; United States National Institutes of Health; Vasodilation; aged; body system; glycosylated-nitric oxide complex hemoglobin A; human data; improved; in vivo; insight; mouse model; novel; oxidant stress; pre-clinical; research study; response to injury; stem; tool; vascular endothelial dysfunction; volunteer

DESCRIPTION (provided by applicant): The overall goal of this project is to improve the safety and efficacy of transfusion of stored blood. There is good evidence that red blood cell storage results in loss of functionality and integrity of red blood cells over time and that this contributes to deleterious effects upon blood transfusion. This project, which is a competitive renewal of a previously funded one, is built around the hypothesis that this storage lesion is largely due to dysregulation of nitric oxide homeostasis in the blood. This disruption is due to increased nitric oxide scavenging by cell-free hemoglobin and microparticles that are released during hemolysis in stored blood and diminished nitric oxide production by the newly discovered red cell nitric oxide synthase. In this renewal we will examine the exact mechanisms of loss of NO bioavailability, as well as down-stream effects of this loss, particularly platelet activation. e will also study interactions that occur in a susceptible host receiving the transfusion. A vast array of clinical, biophysical, molecular biology, and biochemical tools will be applied to characterize the nitric oxide storage lesion in vitro in stored blood as well as in chimeric mice models, a canine model, and in human studies. In addition, therapeutics will be explored in these systems that could restore nitric oxide homeostasis by increasing nitric oxide production.

描述（由申请人提供）：该项目的总体目标是提高储存血液输血的安全性和功效。有充分的证据表明，红细胞储存会导致红细胞的功能丧失和完整性，这会导致对输血的有害影响。该项目是对先前资助的项目的竞争更新，它围绕以下假设：该储存病变主要是由于血液中一氧化氮稳态的失调。这种破坏是由于一氧化氮通过无细胞的血红蛋白和微粒清除，这些氧化物在溶血期间释放的储存血液中释放出来，并通过新发现的红色细胞一氧化氮合酶减少一氧化氮的产生。在这种续约中，我们将研究无生物利用度丧失的确切机制，以及这种损失的下流效应，尤其是血小板激活。 E还将研究接受输血的易感宿主中发生的相互作用。将应用大量的临床，生物物理，分子生物学和生化工具来表征储存的血液以及嵌合小鼠模型，犬类模型以及人类研究中的一氧化氮储存病变。此外，将在这些系统中探索治疗剂，这些系统可以通过增加一氧化氮的产生来恢复一氧化氮的稳态。