Impact of Anemia and Its Treatment on Gut Injury in Preterm Infants

贫血及其治疗对早产儿肠道损伤的影响

• 批准号: 10035140
• 负责人: CASSANDRA D JOSEPHSON
• 金额: $ 61.22万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10035140
• 关键词: Adverse effects; Anemia; Blood; Cause of Death; Clinical; Coupled; Data; Development; Differentiation Antigens; Epithelial; Epithelium; Erythrocyte Transfusion; Erythrocytes; Erythroid; Erythropoiesis; Excision; Exhibits; FABP2 gene; Functional disorder; Hemoglobin; Hypoxia; Hypoxia Inducible Factor; Immune; Impairment; Infant; Inflammation; Inflammatory; Injury; Interferon Type II; Intervention; Intestinal Diseases; Intestines; Investigation; Lead; Leukocyte L1 Antigen Complex; Macrophage Activation; Measures; Mesentery; Mus; Near-Infrared Spectroscopy; Necrotizing Enterocolitis; Neonatal; Neonatal Anemia; Observational Study; Oxygen; Plasma; Pre-Clinical Model; Premature Birth; Premature Infant; Production; Prospective cohort; Prospective cohort study; Reporting; Risk; Role; Safety; Serum; Testing; Tissues; Transfusion; Umbilical Cord Blood; Venous blood sampling; Welding; base; cytokine; high risk; immune function; individual variation; inflammatory disease of the intestine; insight; intestinal barrier; intestinal injury; macrophage; monocyte; mouse model; neonatal immunity; neonate; novel; pre-clinical; preterm newborn; progenitor; prospective; recombinant human erythropoietin; response; urinary

Summary: Treatment of neonatal anemia is largely based on measured hemoglobin concentrations (Hb). Historically, neonatologists developed a conservative approach to blood management, using lower Hb thresholds to trigger transfusions. However, our recent multicenter prospective cohort investigation demonstrated that significant anemia in preterm infants (Hb ≤8g/dL) is associated with the development of necrotizing enterocolitis (NEC), a serious intestinal disease and major cause of death in preterm neonates. Our long-term objective is to identify key mechanisms that regulate anemia-induced alterations in neonatal immunity that contribute to gut inflammation and injury and thus may predispose neonates to inflammatory conditions such as NEC. Our central hypothesis is that variability in anemia-induced alterations in immunosuppressive erythroid progenitors (IEPs) and hypoxia-induced inflammation can differentially impact immune function in the gut, directly predisposing neonates to gut injury that may cause NEC. Our hypothesis is formulated on the basis of our recent discovery that severe anemia in preterm infants can result in impaired gut oxygenation, as measured by near infrared spectroscopy (NIRS), and significantly increased serum levels of pro-inflammatory interferon gamma (IFNg). Using a preclinical model, our data also demonstrate that anemia drives IFNg production by intestinal macrophages that induces intestinal injury, consistent with previous studies that demonstrate that IFNg can directly compromise epithelial barrier function. Importantly, anemia also induces the development of erythroid progenitors, which not only possess the ability to facilitate increased red blood cell (RBC) production, but also appear to be intrinsically immunosuppressive. Consistent with this, IEPs isolated from cord blood possess the ability to suppress macrophage activation, while removal of IEPs in our pre-clinical model exacerbates anemia- induced gut macrophage activation and intestinal injury. Taken together, these results suggest that individual variation in the hypoxic response to lower Hb values, coupled with alterations in anemia-induced IEP numbers and function, creates imbalances that alter local macrophage activity leading to distinct responses in the gut that predispose neonates to intestinal inflammation and place them at higher risk of NEC. To test our central hypothesis, we will pursue the following specific aims: Aim 1: Define the correlation between anemia and its treatment on IEP number and function, and how these relate to serum cytokines, pro-inflammatory monocyte differentiation, and markers of intestinal oxygenation, inflammation, and injury. Aim 2: Define the impact of anemia-induced IEPs on macrophage pro-inflammatory cytokine secretion, intestinal inflammation and injury following different thresholds, durations and treatments of anemia in a pre-clinical model. We think these aims provide a unique opportunity to define key factors that regulate anemia-induced alterations in intestinal inflammation and injury. In doing so, these data possess the capacity to provide important insight into the global immune impact of anemia on neonatal intestinal injury that may contribute to NEC.

摘要：新生儿贫血的治疗主要基于测量的血红蛋白浓度（HB）。 从历史上看，新生儿学家使用较低的HB阈值开发了一种保守的血液管理方法 触发输血。但是，我们最近的多中心前瞻性队列调查表明， 早产儿（Hb≤8g/dl）的明显贫血与坏死性小肠结肠炎的发展有关 （NEC），一种严重的肠道疾病和早产新生儿的主要死亡原因。我们的长期目标是 确定调节贫血引起的新生儿免疫改变的关键机制，这有助于肠道 炎症和损伤，因此可能使新生儿诱发炎症状况，例如NEC。我们的中心 假设是贫血诱导的免疫抑制性红体祖细胞（IEP）的变化变化 缺氧引起的炎症会对肠道中的免疫功能有所不同，直接倾向于 可能导致NEC的肠道损伤。我们的假设是根据我们最近的发现提出的 早产婴儿中严重的贫血会导致肠道氧合受损，如近保险所衡量 光谱法（NIRS），并显着升高血清促炎干扰素γ（IFNG）的血清水平。 使用临床前模型，我们的数据还表明，贫血驱动肠道IFNG产生 诱发肠道损伤的巨噬细胞与以前的研究一致，这些研究表明IFNG可以 直接妥协上皮屏障功能。重要的是，贫血还会诱导红细胞的发展 祖细胞不仅具有促进红细胞（RBC）产生增加的能力，而且还具有 似乎本质上是免疫抑制的。与此一致，从脐带血中孤立的IEP具有 能够抑制巨噬细胞激活的能力，同时在临床前模型中去除IEP，加剧贫血 - 诱导肠道巨噬细胞激活和肠损伤。综上所述，这些结果表明个人 对较低HB值的低氧反应的变化，再加上贫血引起的IEP数的变化 和功能，会产生失衡，改变局部巨噬细胞活性，从而导致肠道中不同的反应 倾向于新生儿对肠道炎症，并将其处于NEC的较高风险。测试我们的中央 假设，我们将追求以下特定目的：目标1：定义贫血与其之间的相关性 IEP数量和功能的治疗，以及这些与血清细胞因子，促炎单核细胞的关系 分化和肠道氧合，感染和损伤的标记。目标2：定义 贫血引起的巨噬细胞促炎细胞因子分泌，肠道感染和损伤的IEP 遵循不同的阈值，临床前模型中贫血的持续时间和治疗方法。我们认为这些目标 提供了一个独特的机会来定义调节贫血引起的肠道改变的关键因素 影响和伤害。这样，这些数据具有为全球提供重要见解的能力 贫血对可能导致NEC的新生儿肠道损伤的免疫影响。