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

摘要：新生儿贫血的治疗在很大程度上是基于测量的血红蛋白浓度(Hb)。 从历史上看，新生儿科医生开发了一种保守的血液管理方法，使用较低的Hb阈值 来触发输血。然而，我们最近的多中心前瞻性队列调查表明 早产儿严重贫血(Hb≤8g/dL)与坏死性小肠结肠炎的发生有关 NEC是一种严重的肠道疾病，也是早产儿死亡的主要原因。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，这些改变有助于肠道 炎症和损伤，因此可能使新生儿易患炎症性疾病，如NEC。我们的中央 假说是贫血引起的免疫抑制红系祖细胞(IEP)的变化 低氧引起的炎症可以不同程度地影响肠道的免疫功能，直接导致 新生儿肠道损伤，可能引起NEC。我们的假设是根据我们最近的发现提出的。 根据近红外线的测量，早产儿的严重贫血会导致肠道氧合功能受损。 光谱分析(NIRS)，并显著升高血清促炎干扰素-γ(IFNG)水平。 使用临床前模型，我们的数据还表明，贫血通过肠道驱动IFNG的产生 诱导肠道损伤的巨噬细胞，这与先前的研究表明IFNG可以 直接损害上皮屏障功能。重要的是，贫血也会导致红血球的发生。 祖细胞，它不仅具有促进红细胞(RBC)产生的能力，而且还 似乎具有内在的免疫抑制作用。与此一致的是，从脐带血中分离出的免疫球蛋白具有 抑制巨噬细胞激活的能力，而在我们的临床前模型中移除IEP会加剧贫血- 诱导肠道巨噬细胞活化和肠道损伤。综上所述，这些结果表明，个人 低Hb值引起的低氧反应的变化，以及贫血诱导的IEP数量的变化 和功能，造成失衡，改变局部巨噬细胞活动，导致肠道中不同的反应， 使新生儿容易发生肠道炎症，并使他们面临较高的NEC风险。为了测试我们的中央 假设，我们将追求以下具体目标：目标1：确定贫血与其 治疗对IEP数量和功能的影响及其与血清细胞因子、促炎单核细胞的关系 分化，以及肠道氧合、炎症和损伤的标志物。目标2：确定 贫血诱导的IEPs对巨噬细胞促炎细胞因子分泌、肠道炎症和损伤的影响 在临床前模型中遵循不同的贫血阈值、持续时间和治疗方法。我们认为这些目标 提供一个独特的机会来确定调节贫血引起的肠道改变的关键因素 炎症和损伤。在这样做的过程中，这些数据具有提供对全球 贫血对新生儿肠道损伤的免疫影响可能有助于NEC的发生。

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.