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

项目摘要 贫血是早产儿中几乎普遍的诊断，主要由医疗必需的静脉切开术引起。 尽管子宫外环境中的不成熟所固有的各种因素也加剧了这一问题。当 严重到需要红细胞输注治疗，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），一种以巨噬细胞 在妊娠22至28周之间出生的人中，这是一个主要的死亡原因。我们最近 阐明了贫血和NEC之间的联系，特别是“漏肠”表现， 巨噬细胞浸润，RBC输注相关的浸润巨噬细胞活化，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， 新生儿肝脏及其在红细胞输注期间对肠粘膜损伤的贡献。我们的初步研究使用 我们现有的临床前小鼠贫血模型表明，贫血与一种新的免疫抑制剂的募集有关。 表达触发的髓样受体1（trem 1）的单核细胞（CD 11bhiF 4/80 midLy 6Cmid）的独特群体， 与新生儿肝脏中发育的单核细胞相似，但与骨髓或脾脏中的单核细胞不同。一致 因此，新生儿贫血的肝单核细胞对血红素显示出更大的炎症激活（在储存的 红细胞）比骨髓来源的细胞。这种炎症反应可以通过使用 抗TREM 1抗体治疗或通过沉默单核细胞TREM 1表达。总的来说，调查人员 我提出了一个新的假设，即在贫血的情况下，肠-肝-肠的回飞棒效应被认为是肠道的渗漏， 贫血期间肠道和相关细菌移位通过门静脉与肝脏沟通， 原位形成的肝白细胞群扩大，进而浸润贫血肠， 易患红细胞相关的肠道损伤为了检验我们的中心假设，我们将继续研究以下具体问题。 目的：目的1：阐明贫血时巨噬细胞向新生儿肠道募集的个体发生。目标二： 明确trem 1信号在肝单核细胞向贫血肠迁移中的作用，以及在 红细胞输注期间的炎症激活。目的3：确定治疗靶向是否为肝 贫血期间Trem 1+单核细胞可以预防/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细胞凋亡的治疗策略。 贫血期间的免疫应答，而不抑制保护性先天免疫机制。

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.