Erythrocyte Transfusion in Acute Lung Injury During Sepsis

描述（由申请人提供）：红细胞输注是危重病人的常规输注。最近的流行病学研究表明，红细胞输注与肺损伤的发展、危重患者发病率和死亡率的增加有关。这种关联的病因仍不确定，因为白细胞减少的临床益处尚未得到令人信服的证明。本研究的主要前提是输血红细胞浓缩物的非白细胞成分可使受者在败血症期间易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，纯化红细胞输注促进肺中性粒细胞积累。本研究的主要目的是确定脓毒性炎症期间输注纯化红细胞是否会通过活性氧（ROS）的产生、内皮细胞活化和肺损伤导致氧化应激增加。在特异性目的1中，我们将确定红细胞浓缩物的非白细胞成分是否能促进脓毒症小鼠模型中中性粒细胞介导的肺损伤。在特异性目标2中，我们将在体外确定红细胞浓缩物对内皮细胞活化、中性粒细胞-内皮粘附和跨内皮迁移的影响。在特异性目标3中，我们将使用缺乏NADPH氧化酶活性的gp47缺失小鼠，在体外和体内模型中研究红细胞输注对活性氧ROS产生的影响。从这些研究中获得的知识可能阐明红细胞输血后果的一种机制，并为危重患者的常见问题提供新的见解。

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.