Erythrocyte Transfusion in Acute Lung Injury During Sepsis

脓毒症期间急性肺损伤的红细胞输注

• 批准号: 7406981
• 负责人: Nilam S. Mangalmurti
• 金额: $ 5.67万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7406981
• 关键词: Acute; Acute Lung Injury; Adhesions; Adult Respiratory Distress Syndrome; Anemia; Antioxidants; Cell Adhesion Molecules; Cells; Clinical; Critical Illness; Daily; Defense Mechanisms; Development; Disruption; Endothelial Cells; Epidemiologic Studies; Equilibrium; Erythrocyte Transfusion; Erythrocytes; Etiology; Free Radicals; Generations; Goals; Hemoglobin; Homeostasis; Host Defense; Immune response; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Intensive Care Units; Ischemia; Knockout Mice; Knowledge; Lead; Leukocytes; Lipids; Lung; Lung Inflammation; Mediating; Mediator of activation protein; Membrane; Modeling; Morbidity - disease rate; Mus; NADPH Oxidase; Neutrophil Activation; Neutrophil Infiltration; Oxidative Stress; Oxygen; Patients; Personal Satisfaction; Production; Proteins; Reactive Oxygen Species; Sepsis; Source; Transfusion; Vascular Permeabilities; cell injury; cytokine; in vivo; in vivo Model; insight; lung injury; migration; mortality; mouse model; neutrophil; novel strategies; oxidation; septic

DESCRIPTION (provided by applicant): Red blood cell transfusions are routinely given to critically ill patients. Recent epidemiological studies have shown that red cell transfusions are associated with the development of lung injury, increased morbidity and mortality in the critically ill. The etiology underlying this association remains uncertain, as a clinical benefit has not been convincingly demonstrated with leukoreduction. The main premise of this study is that transfusion of the non-leukocyte component of red cell concentrates can pre-dispose the recipient to acute lung inflammation and injury during sepsis. We have developed an in vivo murine model whereby purified erythrocyte transfusion promotes neutrophilic accumulation in the lungs. The main goal of this proposal is to determine whether transfusion of purified erythrocytes during septic inflammation can lead to increased oxidative stress through the generation of reactive oxygen species (ROS), endothelial cell activation and lung injury. In Specific Aim 1 we will determine whether the non-leukocyte component of red cell concentrates can promote neutrophil mediated lung injury in a mouse model of sepsis. In Specific Aim 2, we will determine the impact of erythrocyte concentrates on endothelial cell activation, neutrophil-endothelial adhesion, and trans- endothelial migration in vitro. In Specific Aim 3, we will examine the effects of erythrocyte transfusions on the generation of reactive oxygen species ROS both in vitro and in our in vivo model using gp47 null mice deficient in NADPH oxidase activity. Knowledge derived from these studies may elucidate one mechanism underlying the consequences of red cell transfusion and provide new insight to a common problem in the critically ill.

描述（由申请人提供）：红细胞输注常规给予危重患者。最近的流行病学研究表明，红细胞输注与肺损伤的发生、危重患者发病率和死亡率的增加有关。这种相关性的病因仍不确定，因为尚未令人信服地证明白细胞减少的临床益处。本研究的主要前提是，输注红细胞浓缩物的非白细胞成分可使受者在脓毒症期间易于发生急性肺部炎症和损伤。我们已经开发了一种体内小鼠模型，其中纯化的红细胞输注促进嗜酸性粒细胞在肺中的积累。本提案的主要目标是确定在脓毒性炎症期间输注纯化红细胞是否会通过产生活性氧（ROS）、内皮细胞活化和肺损伤导致氧化应激增加。在具体目标1中，我们将确定红细胞浓缩物的非白细胞组分是否可以促进脓毒症小鼠模型中中性粒细胞介导的肺损伤。在具体目标2中，我们将确定红细胞浓缩物对体外内皮细胞活化、嗜中性粒细胞-内皮粘附和跨内皮迁移的影响。在特定目标3中，我们将使用NADPH氧化酶活性缺陷的gp 47敲除小鼠，在体外和体内模型中检查红细胞输注对活性氧ROS生成的影响。从这些研究中获得的知识可能阐明红细胞输注后果的一种机制，并为危重患者的常见问题提供新的见解。