Harmful effects of transfusion of older stored red cells: iron and inflammation

输入较旧储存红细胞的有害影响：铁和炎症

• 批准号: 8111203
• 负责人: STEVEN L SPITALNIK
• 金额: $ 49.21万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-17 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8111203
• 关键词: Acute; Adult; Adverse effects; Blood; Blood Transfusion; Blood donor; Chelating Agents; Chronic; Clinical; Clinical Research; Critical Illness; Disease; Dose; Endotoxins; Epidemiologic Studies; Erythrocytes; Exposure to; FDA approved; Foundations; Future; Goals; Hematological Disease; Hemoglobin; Hemoglobinopathies; Hour; Human; Human Volunteers; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Inflammatory Response Pathway; Infusion procedures; Institutional Review Boards; Iron; Iron Chelating Agents; Kidney; Lead; Length of Stay; Lipopolysaccharides; Liver; Medicine; Modeling; Mus; Operative Surgical Procedures; Organ failure; Patients; Prospective Studies; Reactive Oxygen Species; Research; Reticuloendothelial System; Role; Sepsis; Sepsis Syndrome; Sickle Cell; Sickle Cell Anemia; Spleen; Staging; System; Testing; Thalassemia; Therapeutic; Time; Transfusion; base; beta Thalassemia; cytokine; design; healthy volunteer; human disease; improved; innovation; insight; macrophage; meetings; monocyte; mortality; mouse model; novel; pre-clinical; preclinical study; prevent; senescence; septic

DESCRIPTION (provided by applicant): Epidemiological studies show that the transfusion of older stored blood is associated with increases in mortality, serious infections, multi-organ failure, and hospital length of stay. Our research is based on the overarching hypothesis that the adverse effects of the transfusion of stored blood result from the acute delivery of hemoglobin iron to the monocyte-macrophage system. By current FDA standards, a unit of stored red blood cells (RBC) is clinically acceptable for transfusion if as much as 25% of the RBC is cleared within 24 hours, thereby delivering a substantial dose of iron to the monocyte-macrophage system. We hypothesize that the pro-oxidant effects exerted by acute exposure to these massive amounts of hemoglobin iron induce a pro- inflammatory cytokine response that may lead to the serious consequences seen in human studies. Our pre- clinical studies using a well-characterized mouse model demonstrate that the transfusion of older stored RBC acutely delivers hemoglobin iron to the spleen, kidney, and liver, induces an intense pro-inflammatory cytokine response, and synergizes with the effects of endotoxin (a standard sepsis model) to enhance and prolong cytokine storm. Therefore, the main goal of the current proposal is to establish the relevance of these novel pre-clinical observations in humans. To this end, we propose carefully-controlled, prospective studies of healthy volunteers and patients with hemoglobinopathies. We will first study healthy individuals to avoid the confounding factors present in prior studies of critically-ill or surgical patients that examined whether transfusions of older stored RBC produce adverse effects. We will then extend these findings to two relevant human disease settings, by studying stable patients with either sickle cell disease or beta-thalassemia who regularly receive simple transfusions. Because these patients are treated with chronic iron-chelating therapy, which can be safely discontinued for short periods of time, this will allow us to evaluate our novel hypothesis implicating the role of acute iron delivery. Aim #1 will test the hypothesis that transfusion of older stored RBC into healthy human volunteers induces an acute pro-inflammatory cytokine response. Aim #2 will test the hypothesis that transfusion of older stored RBC induces an acute pro-inflammatory response in chronically transfused patients with either sickle cell disease or beta-thalassemia. In addition, we will determine whether other standard RBC products often used in this setting (i.e. washed RBC and cryopreserved RBC) induce similar effects. Finally, Aim #3 will test the hypothesis that treating sickle cell disease and beta-thalassemia patients with iron chelators will prevent the acute pro- inflammatory response induced by transfusing older stored RBC. The insights gained from completing this proposal will have an immediate impact on the current practice of transfusion medicine and will provide the foundation for developing rationally-designed approaches to improve the quality of human donor RBC and of human transfusion therapy.

描述（由申请人提供）： 流行病学研究表明，较老的血液的输血与死亡率，严重感染，多器官失败和住院时间的增加有关。我们的研究是基于总体假设，即储存血液输血的不利影响是由于血红蛋白铁急性递送到单核细胞巨噬细胞系统而产生的。按照当前的FDA标准，如果多达25％的RBC在24小时内清除了多达25％的RBC，则可以在临床上接受一个存储的红细胞（RBC）单位，从而向单核细胞巨噬细胞系统提供了大量的铁。我们假设急性暴露于这些大量的血红蛋白铁诱导促炎性细胞因子反应所产生的促氧化作用，这可能会导致人类研究中看到的严重后果。我们使用特征良好的小鼠模型使用的临床研究表明，老年储存的RBC的输血急性将血红蛋白铁递送到脾脏，肾脏和肝脏中，诱导了强烈的促炎细胞因子反应，并随着内毒素（标准的SEPIS模型）的影响，以增强cytokine cytokoknogn cytokokenong cytokokoke cytokokoke cytokok cytokoke cy。因此，当前建议的主要目标是确定这些新型临床前观察的相关性。 为此，我们建议对健康志愿者和血红蛋白病患者进行精心控制的前瞻性研究。我们将首先研究健康的个体，以避免对批判性ILL或外科患者的先前研究中存在的混杂因素，这些因素检查了较老的RBC输血是否会产生不利影响。然后，我们将通过研究经常接受简单输血的稳定患者或β地中海贫血的稳定患者，将这些发现扩展到两个相关的人类疾病环境。由于这些患者接受了慢性铁授粉疗法的治疗，可以在短时间内安全停止，因此这将使我们能够评估我们的新假设，这意味着急性铁的作用。 AIM＃1将检验以下假设：将较老的RBC输注到健康的人类志愿者中会诱导急性促炎细胞因子反应。 AIM＃2将检验以下假设：较老的RBC输血会引起长期输血患有镰状细胞病或β-丘脑中性疾病的急性促炎反应。此外，我们将确定其他标准的RBC产品在这种情况下是否经常使用（即洗涤的RBC和冷冻保存RBC）会引起类似的效果。最后，AIM＃3将检验以下假设：用铁螯合剂治疗镰状细胞疾病和β-丘脑贫血患者将防止输血旧储存的RBC引起的急性促炎性反应。从完成该提案中获得的见解将对当前的输血医学实践产生直接影响，并将为开发合理设计的方法提供基础，以提高人类捐助者RBC和人类输血疗法的质量。