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

• 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
• 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

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 对于早产儿和危重病患者来说，输注红细胞（RBCT）是必要的，可以挽救生命 由于生理和医源性因素导致严重贫血的患病婴儿。最近， 我们已经表明严重贫血与肠通透性增加有关， 通过血液中内毒素的鉴定得到证实。此外还有 提高对血库储存这一必要步骤的危险性的认识， 输血储存的红细胞的输注被肝脏巨噬细胞迅速清除， 非转铁蛋白结合铁（NTBI）在血浆中循环，通过 组织中的铁沉积。在关键发育期间发生严重贫血的风险 期间必须与输血的风险相平衡，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）。的 贫血和输血直接或间接与 SIRS的发展仍不清楚。红细胞与高脂血症之间关系的批判性评价 输血和SIRS是必要的，以改善临床实践和发展的治疗策略 预防和/或改善贫血-RBCT相关SIRS。研究RBCT相关 研究人员使用现有的小鼠模型，其中10天大的小鼠幼崽被 在出生后第2-10天（P）进行定时放血，以诱导严重贫血 （血细胞比容18%-22%），此时他们接受静脉输注RBC，然后 观察时间长达24小时。根据初步数据，研究人员提出了一个新的假设， 贫血的新生儿是唯一易患SIRS的，因为 由于肠屏障功能丧失， 肝单核细胞对预先形成的细胞因子的反应; RBCT可以加强这种作用。那里 有两个具体目标：（1）确定新生儿肝脏（NL）源性的病理生理作用， 单核细胞在贫血和红细胞输注期间SIRS的发展中的作用。(2)确定 无论是阻断肝脏单核细胞上的TREM 1活性和/或恢复贫血相关的 肠通透性可预防/改善输血相关贫血 SIRS。拟议目标的实现将说明这些机制和潜力 预防和/或治疗危重病患者贫血-RBCT输血相关SIRS的策略 新生儿。