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

新生儿贫血中的肝肠轴及其在红细胞输注相关肠道损伤中的作用

基本信息

批准号：
10834574
负责人：
Mohan Kumar Krishnan
金额：
$ 49.63万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-20 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10834574
关键词：
Adoptive Cell Transfers Adult Adverse effects Anemia Antibody Therapy Attenuated Awareness Bacterial Translocation Bone Marrow Caring Cells Communication Data Diagnosis Dose Embryo Endothelium Enterobacteria phage P1 Cre recombinase Environment Epithelium Erythropoietin Fetal Liver Fetus Growth Gut Mucosa Hematopoiesis Heme Hepatic Human ITGAM gene Immunity In Situ Infiltration Inflammatory Inflammatory Response Injury Intervention Intestinal Mucosa Intestinal permeability Intestines Leaky Gut Leukocytes Lipopolysaccharides Liver Macrophage Maps Medical Morbidity - disease rate Mucous Membrane Mus Myelogenous Myeloid Cells Natural Immunity Necrosis Necrotizing Enterocolitis Neonatal Neonatal Anemia Oxygen Pathologic Peptides Phenotype Physiological Population Portal vein structure Pregnancy Premature Infant Probability Research Personnel Risk Role Severities Signal Transduction Site Source Spleen Surface Testing Transact Transfusion Venous blood sampling gut-liver axis inducible Cre inhibitor innate immune mechanisms intestinal hypoxia intravenous administration migration monocyte mortality mouse model necrotic tissue neonatal mice neonate novel postnatal pre-clinical preterm newborn prevent receptor recruit response therapeutic target therapeutically effective

Adoptive Cell Transfers Adult Adverse effects Anemia Antibody Therapy Attenuated Awareness Bacterial Translocation Bone Marrow Caring Cells Communication Data Diagnosis Dose Embryo Endothelium Enterobacteria phage P1 Cre recombinase Environment Epithelium Erythropoietin Fetal Liver Fetus Growth Gut Mucosa Hematopoiesis Heme Hepatic Human ITGAM gene Immunity In Situ Infiltration Inflammatory Inflammatory Response Injury Intervention Intestinal Mucosa Intestinal permeability Intestines Leaky Gut Leukocytes Lipopolysaccharides Liver Macrophage Maps Medical Morbidity - disease rate Mucous Membrane Mus Myelogenous Myeloid Cells Natural Immunity Necrosis Necrotizing Enterocolitis Neonatal Neonatal Anemia Oxygen Pathologic Peptides Phenotype Physiological Population Portal vein structure Pregnancy Premature Infant Probability Research Personnel Risk Role Severities Signal Transduction Site Source Spleen Surface Testing Transact Transfusion Venous blood sampling gut-liver axis inducible Cre inhibitor innate immune mechanisms intestinal hypoxia intravenous administration migration monocyte mortality mouse model necrotic tissue neonatal mice neonate novel postnatal pre-clinical preterm newborn prevent receptor recruit response therapeutic target therapeutically effective

展开

项目摘要

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.

项目摘要贫血是早产儿几乎普遍的诊断，主要是由医疗必不可少的静脉切开术护理，尽管在前子宫环境中继承了多种因素的因素也加剧了护理。什么时候临床医生必须意识到严重治疗的重度以接受RBC输血的治疗例如坏死性小肠结肠炎（NEC），一种以巨噬细胞为特征的炎症性肠坏死在22至28周妊娠之间出生的人的浸润和死亡的主要原因。我们最近有阐明了贫血与NEC之间的联系，特别是以巨噬细胞浸润，RBC输血相关的浸润巨噬细胞的激活，并产生肠粘膜损伤。我们的长期目标是研究贫血引起的免疫力变化新生儿肝及其对RBC输血期间对肠道粘膜损伤的贡献。我们使用的初步研究我们现有的贫血前临床前鼠模型表明，贫血与招募有关单核细胞（CD11BHIF4/80 -MIDLY6CMID）的独特群体触发髓样受体1（Trem1），类似于新生儿肝脏中发育的单核细胞，但与骨髓或sleen中的单核细胞不同。持续的因此，新生儿贫血肝单核细胞显示出更大的炎症激活对血红素（发现 rbc）比骨髓衍生的细胞。这种炎症反应可以通过使用抗Trem1抗体处理或通过沉默单核细胞TREM1表达。两者一起，调查人员提议一种新的假设，即在贫血的情况下，肠肝双向飞旋镖效应被认为是泄漏的贫血和相关细菌在贫血期间通过门静脉传播到肝脏，触发肝清白细胞种群的扩大原位发展，这些人口继续渗透到麻醉肠道上，倾向于与RBC相关的肠道损伤。为了检验我们的中心假设，我们将追求以下特定的特定目的：目标1：阐明在贫血期间募集到新生儿肠道的巨噬细胞的个体发育。目标2：定义TREM1信号传导对肝单核细胞迁移到麻醉肠的迁移的作用，并在 RBC输血期间的炎症激活。 AIM 3：确定肝的热靶向是否贫血期间的TREM1+单核细胞可以预防/衰减RBC输液相关的NEC样损伤。提议的目标的完成将制定有效的理论策略，以抑制肝贫血期间的反应，而没有抑制受保护的先天免疫组机制。