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治疗方法。最近的流行病学研究表明，在危重病人中，红细胞输注与肺损伤的发生、发病率和死亡率的增加有关。这种联系背后的病因仍然不确定，因为临床上的好处还没有在白细胞减少中得到令人信服的证明。这项研究的主要前提是，输注浓缩红细胞中的非白细胞成分可以使受者在脓毒症期间发生急性肺部炎症和损伤。我们已经建立了一个体内的小鼠模型，通过输注纯化的红细胞促进中性粒细胞在肺部的聚集。这项建议的主要目的是确定在脓毒症炎症期间输注纯化的红细胞是否会通过产生活性氧(ROS)、内皮细胞激活和肺损伤而导致氧化应激增加。在特定的目标1中，我们将确定红细胞浓缩物中的非白细胞成分是否可以促进中性粒细胞介导的败血症小鼠模型的肺损伤。在特定的目标2中，我们将确定红细胞浓缩物在体外对内皮细胞激活、中性粒细胞-内皮细胞黏附和跨内皮细胞迁移的影响。在具体目标3中，我们将在体外和我们的体内模型中，以NADPH氧化酶活性缺失的gp47缺失小鼠为对象，研究红细胞输注对ROS生成的影响。从这些研究中获得的知识可能会阐明一种潜在的红细胞输注后果的机制，并为危重病人的一个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.