RBC TRANSFUSION IN ANEMIC NEONATES LEADS TO SYSTEMIC INFLAMMATORY RESPONSE SYNDROME

贫血新生儿红细胞输注导致全身炎症反应综合征

基本信息

批准号：
10284300
负责人：
Mohan Kumar Krishnan
金额：
$ 24.56万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-06 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10284300
关键词：
Acute Address Adult Anemia Attenuated Bacterial Translocation Biological Blood Blood Banks Blood Circulation Bone Marrow Critical Illness Data Deposition Development Endotoxins Erythrocyte Transfusion Erythrocytes Evaluation Exocytosis Fetus Functional disorder Funding Opportunities Hematocrit procedure Hematopoiesis Heme Hemin Hepatic Hour Human ITGAM gene Iatrogenesis In Situ Infant Inflammation Inflammatory Inflammatory Response Intestinal permeability Intravenous Investigation Iron Knowledge Kupffer Cells Lead Leukocytes Life Lipopolysaccharides Liver Mus Myelogenous Myeloid Cells Myosin Light Chain Kinase Neonatal Neonatal Anemia Organ Peptides Physiological Plasma Population Portal vein structure Pregnancy Production Research Personnel Risk Role Savings Severities Site Source Spleen Surface Syndrome Systemic Inflammatory Response Syndrome Testing Therapeutic Tissues Transfusion Venous blood sampling base clinical practice critical developmental period cytokine cytokine release syndrome experience improved in vivo inhibitor/antagonist insight intestinal barrier intestinal hypoxia kinase inhibitor macrophage monocyte mouse model neonatal mice neonate novel postnatal pre-clinical premature preterm newborn prevent pup receptor response restoration therapeutically effective uptake

项目摘要

Project summary Transfusions of Red Blood Cells (RBCT) are necessary and life-saving in premature and critically ill infants, who experience severe anemia due to both physiologic and iatrogenic factors. Recently, we have shown that severe anemia was associated with increased intestinal permeability, demonstrated by the identification of endotoxin in the bloodstream. Additionally, there is increasing recognition of the dangers of the necessary step of blood bank storage prior to transfusion. Transfusions of stored RBCs are rapidly cleared by liver macrophages, producing non-transferrin bound iron (NTBI) to circulate in plasma, acutely inducing inflammation through iron deposition in tissues. The risks of experiencing severe anemia during critical developmental periods must be balanced with the risks of transfusions, which can lead to Systemic Inflammatory Response Syndrome (SIRS) and potentially Multi Organ Dysfunction Syndrome (MODS). The underlying mechanism(s) by which anemia and transfusion directly or indirectly correlate with the development of SIRS remain unclear. Critical evaluation of the association between RBC transfusion and SIRS is necessary to improve clinical practice and develop therapeutic strategies to prevent and/or ameliorate anemia-RBCT associated SIRS. To investigate RBCT associated SIRS, the investigators used an existing murine model in which 10-day-old mouse pups were subjected to timed phlebotomy between postnatal days (P) 2-10 to induce severe anemia (hematocrits 18%-22%), at which point they received an intravenous RBC transfusion, then observed for up to 24h. Based on preliminary data, the investigators propose a novel hypothesis that anemic neonates are uniquely predisposed to SIRS because of direct transmigration of bacterial products from the hypoxic intestine due to loss of intestinal barrier function, facilitating the hepatic monocyte response with preformed cytokines; RBCT can potentiate this effect. There are two specific aims: (1) Determine the pathophysiological role of neonatal liver (NL)-derived monocytes in the development of SIRS during anemia and RBC transfusion. (2) Determine whether blocking trem1 activity on liver monocyte and/or restoration of anemia-associated intestinal permeability can prevent/ameliorate anemia-transfusion associated SIRS. Accomplishment of the proposed aims will explain the mechanisms and potential strategies to prevent and/or treat anemia-RBCT transfusion associated SIRS in critically-ill neonates.

项目摘要红细胞（RBCT）的输血是必要的，并且在早产和批判性中挽救生命生病的婴儿由于生理和医源性因素而患有严重的贫血。最近，我们已经表明，严重的贫血与肠道通透性增加有关通过鉴定血液中内毒素的鉴定来证明。另外，还有提高对血库存储步骤的危险的认识输血。肝巨噬细胞迅速清除了储存的RBC的输血，产生非转铁蛋白结合的铁（NTBI）在血浆中循环，急性诱导通过铁沉积在组织中。在关键发展期间经历严重贫血的风险时期必须与输血的风险保持平衡，这可能导致全身性炎症反应综合征（SIRS）和潜在的多器官功能障碍综合征（MODS）。这贫血和输血直接或间接与之相关的基本机制先生的发展尚不清楚。对RBC之间关联的批判性评估输血和SIRS对于改善临床实践和制定治疗策略是必要的预防和/或改善贫血-RBCT相关的SIR。研究RBCT相关先生，研究人员使用了现有的鼠模型，其中10天大的小鼠幼崽是在产后天（P）2-10之间进行定时的静脉切开术，以诱发严重的贫血（血细胞比容18％-22％），此时他们接受了静脉注射RBC输血，然后观察到长达24小时。根据初步数据，研究人员提出了一个新的假设由于直接移民的直接移民由于肠道屏障功能的丧失，来自低氧肠的细菌产物，促进肝单核细胞的反应与预成立的细胞因子； RBCT可以增强这种效果。那里是两个具体的目的：（1）确定新生儿肝（NL）衍生的病理生理作用在贫血和RBC输血期间SIRS发育中的单核细胞。（2）确定是否阻断肝单核细胞上的TREM1活性和/或与贫血相关的恢复肠道通透性可以预防/改善贫血转移相关先生。提议的目标的完成将解释机制和潜力预防和/或治疗贫血 - rbct输血相关的SIRS的策略新生儿。