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

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，血液学家开发了一种保守的血液管理方法，使用较低的Hb阈值 触发输血然而，我们最近的多中心前瞻性队列研究表明， 早产儿严重贫血（Hb ≤ 8 g/dL）与坏死性小肠结肠炎的发生相关 (NEC)这是一种严重的肠道疾病，也是早产儿死亡的主要原因。我们长远的目标是 确定调节贫血诱导的新生儿免疫改变的关键机制， 炎症和损伤，因此可能使新生儿易患炎性疾病，如NEC。我们的中央 一种假说是贫血诱导免疫抑制性红系祖细胞（IEPs）改变的可变性 缺氧引起的炎症可以不同程度地影响肠道的免疫功能， 新生儿肠道损伤可能导致NEC。我们的假设是根据我们最近的发现提出的 早产儿的严重贫血会导致肠道氧合受损，如近红外测量的那样， 结果显示，在近红外光谱（NIRS）下，血清中促炎性干扰素γ（IFNg）水平显著升高。 使用临床前模型，我们的数据还表明，贫血驱动肠道IFNg的产生， 这与先前的研究一致，即IFNg可以诱导肠损伤， 直接损害上皮屏障功能。重要的是，贫血还诱导红系细胞的发育， 祖细胞，其不仅具有促进增加的红细胞（RBC）产生的能力，而且 似乎具有免疫抑制作用。与此一致，从脐带血中分离的IEPs具有 抑制巨噬细胞活化的能力，而在我们的临床前模型中去除IEPs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， 对较低Hb值的缺氧反应的变化，以及贫血诱导的IEP数量的改变 和功能，造成不平衡，改变局部巨噬细胞的活动，导致不同的反应，在肠道， 使新生儿易患肠道炎症，并使他们处于NEC的更高风险中。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：定义贫血与其 治疗对IEP数量和功能的影响，以及这些与血清细胞因子、促炎单核细胞 分化，以及肠氧合、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 根据临床前模型中贫血的不同阈值、持续时间和治疗。我们认为这些目标 提供了一个独特的机会，以确定关键因素，调节贫血引起的肠道改变， 炎症和损伤。在这样做的时候，这些数据有能力提供重要的洞察力， 贫血对可能导致NEC新生儿肠道损伤的免疫影响

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.