Liver-Gut Axis in Neonatal Anemia and Its Role in RBC Transfusion Associated Gut Injury

项目总结 在早产儿中，贫血几乎是一种普遍的诊断，主要是由医学上必不可少的静脉切割术引起的 尽管体外环境中的不成熟所固有的各种因素也加剧了这一问题，但也加剧了这一问题。什么时候 严重到可以用红细胞输注治疗，临床医生必须意识到严重不良反应的风险。 例如坏死性小肠结肠炎(NEC)，这是一种以巨噬细胞为特征的炎症性肠坏死 在妊娠22周至28周之间出生的人中，渗透是导致死亡的主要原因。我们最近做了 阐明了贫血和NEC之间的联系，特别是“肠漏”的表现，其特征是 巨噬细胞的渗入、红细胞输注对渗入的巨噬细胞的相关激活以及由此产生的 肠粘膜损伤。我们的长期目标是研究贫血引起的免疫变化 新生儿肝脏在输注红细胞过程中对肠粘膜损伤的影响我们的初步研究使用 我们现有的临床前贫血小鼠模型表明，贫血与新生的 单核细胞(CD11bhiF4/80midLy6Cmid)的独特群体，表达触发的髓系受体1(Tem1)， 类似于在新生儿肝脏中发育的单核细胞，但不同于在骨髓或脾中的单核细胞。一致 在这一点上，新生儿贫血的肝单核细胞对血红素(在储存的 RBC)，而不是骨髓来源的细胞。这种炎症反应可以通过使用以下两种方法来抑制 抗tem1抗体治疗或通过沉默单核细胞trem1的表达。总而言之，调查人员 提出一种新的假设，即在贫血的情况下，肠道-肝脏-肠道的回旋镖效应被记录为渗漏 在贫血期间肠道和相关细菌移位通过门静脉传递到肝脏，触发 原位发育的肝白细胞群扩张，进而渗透到贫血的肠道， 易患红细胞相关性肠道损伤。为了测试我们的中心假设，我们将进行以下具体操作 目的：目的1：阐明贫血时巨噬细胞在新生儿肠道中的个体发育。目标2： 明确信号转导通路在肝单核细胞向贫血肠道的迁移过程中的作用 红细胞输注过程中的炎症激活。目的3：确定肝靶向治疗是否 贫血时的单核细胞可预防/减轻RBC输注相关的NEC样损伤。 所提出的目标的实现将开发一种有效的抑制肝脏的治疗策略。 在不抑制保护性先天免疫机制的情况下，在贫血期间的反应。

Project summary Anemia is a nearly universal diagnosis in preterm infants, caused primarily by phlebotomy essential for medical care, though also exacerbated by a variety of factors inherent to immaturity in the ex utero environment. When severe enough to be treated with RBC transfusion, clinicians must be aware of the risk of critical adverse effects such as necrotizing enterocolitis (NEC), an inflammatory bowel necrosis characterized by macrophage infiltration, and a leading cause of mortality in those born between 22 and 28 weeks gestation. We have recently elucidated the connection between anemia and NEC, specifically, the “leaky gut” presentation characterized by macrophage infiltration, RBC transfusion-associated activation of infiltrated macrophages, and the resulting intestinal mucosal injury. Our long-term objective is to study the anemia-induced immunity changes in the neonatal liver and their contribution to gut mucosal injury during RBC transfusion. Our preliminary studies using our existing pre-clinical murine model of anemia demonstrate that anemia is associated with recruitment of a unique population of monocyte (CD11bhiF4/80midLy6Cmid) expressing triggered myeloid receptor 1 (trem1), similarly to monocytes developing in the neonatal liver but unlike those in the bone marrow or spleen. Consistent with this, neonatal anemic liver monocytes displayed greater inflammatory activation to heme (found in stored RBC) than did bone-marrow derived cells. This inflammatory response could be dampened either by the use of anti-trem1 antibody treatment or by silencing monocyte trem1 expression. Taken together, the investigators propose a novel hypothesis that in the setting of anemia, a gut-liver-gut boomerang effect is noted as the leaky gut and associated bacterial translocation during anemia communicate via the portal vein to the liver, trigger the expansion of hepatic leukocyte populations developing in situ which proceed to infiltrate the anemic intestine, predisposing to RBC-associated gut injury. To test our central hypothesis, we will pursue the following specific aims: Aim 1: Elucidate the ontogeny of macrophages recruited to the neonatal intestine during anemia. Aim 2: Define the role of trem1 signaling on the migration of hepatic monocytes into the anemic intestine, and on the inflammatory activation during RBC transfusion. Aim 3: Determine whether therapeutic targeting of hepatic trem1+ monocytes during anemia can prevent/ attenuate RBC-transfusion associated NEC-like injury. Accomplishment of the proposed aims will develop an effective therapeutic strategy of inhibiting the hepatic response during anemia without suppressing protective innate immune mechanisms.