Harmful effects of red blood cell transfusions are mediated by iron

描述（由申请人提供）：本项目将检查红细胞（RBC）储存时间对感染并发症风险较高的患者输血安全性的影响，例如创伤，手术或进入重症监护室后。越来越多的证据表明，输血储存14天或更长时间的血液与住院患者的感染率，发病率和死亡率增加有关。在体外储存期间，RBC经历累积的生物化学和生物力学变化，这降低了它们在体内的存活。输血后，储存受损的RBC通常在第一个小时内被网状内皮巨噬细胞从循环中迅速清除。然后，这种RBC血红蛋白铁被快速分解代谢，并以超过转铁蛋白（生理铁转运蛋白）摄取速率的速度返回血浆，从而产生血浆非转铁蛋白结合铁，其可以刺激微生物生长。我们的总体假设是，长期储存后输注RBC会导致循环非转铁蛋白结合铁的急性升高，这会通过促进微生物病原体的生长而增加感染性并发症的风险。为此，我们建议对健康志愿者和危重儿科患者进行仔细对照的前瞻性研究。在目标1中，我们将确定健康成人志愿者自体输血后RBC储存持续时间、RBC清除率和循环非转铁蛋白结合铁产生之间的关系。在目标2中，我们将确定在儿科ICU中的危重婴儿和儿童在同种异体红细胞输注后循环非转铁蛋白结合铁的幅度和过程。最后，我们将确定循环非转铁蛋白结合铁是否增强儿科ICU中引起菌血症和脓毒症的临床重要病原体的体外生长。该项目将通过以下方式填补关键知识空白：（i）定义安全的RBC储存间隔，避免产生循环非转铁蛋白结合铁;（ii）定量同种异体移植后危重儿科患者的循环非转铁蛋白结合铁浓度;（iii）确定循环非转铁蛋白结合铁对从儿科患者中分离的临床重要病原体生长的影响。这些新信息将有助于确定提高住院患者红细胞输注安全性的方法。

DESCRIPTION (provided by applicant): This project will examine the effect of the duration of red blood cell (RBC) storage on the safety of transfusion in patients with a heightened risk of infectious complications, such as after trauma, surgery, or admission to an intensive care unit. Accumulating evidence suggests that transfusion of blood stored for 14 days or longer is associated with increased rates of infection, morbidity, and mortality in hospitalized patients. During storage in vitro, RBCs undergo cumulative biochemical and biomechanical changes that reduce their survival in vivo. After transfusion, storage damaged RBCs are quickly cleared from the circulation by reticuloendothelial macrophages, usually within the first hour. This RBC hemoglobin iron is then rapidly catabolized and returned to plasma at a pace that can exceed the rate of uptake by transferrin, the physiologic iron transporter, thereby producing plasma non-transferrin-bound iron, which can stimulate microbial growth. Our overarching hypothesis is that transfusions of RBCs after prolonged storage produce acute elevations of circulating non- transferrin-bound iron, which increase the risk of infectious complications by enhancing the growth of microbial pathogens. To this end, we propose carefully controlled, prospective studies of healthy volunteers and critically ill pediatric patients. In Aim 1, we will determine the relationship between the duration of RBC storage, RBC clearance, and production of circulating non-transferrin-bound iron after autologous transfusion in healthy adult volunteers. In Aim 2, we will determine the magnitude and course of circulating non-transferrin-bound iron after allogeneic RBC transfusions in critically ill infants and children in the Pediatric ICU. Finally, i Aim #3 we will determine whether circulating non-transferrin-bound iron enhances growth in vitro of clinically important pathogens responsible for bacteremia and sepsis in the Pediatric ICU. This project will fill critical gaps in knowledge by (i) defining a safe RBC storage interval that avoids production of circulating non-transferrin- bound iron, (ii) quantifying concentrations f circulating non-transferrin-bound iron in critically ill pediatric patients after allogeneic transfsion, and (iii) determining the effects of circulating non-transferrin-bound iron on the growth of clinically important pathogens isolated from pediatric patients. This new information will help identify ways to improve the safety of RBC transfusions in hospitalized patients.