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

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.

项目概要贫血是早产儿的一种几乎普遍的诊断，主要是由医疗必需的静脉切开术引起的尽管子宫外环境中的不成熟所固有的各种因素也会加剧这种情况。严重到需要进行红细胞输注治疗，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)，一种以巨噬细胞为特征的炎症性肠坏死我们最近发现，渗透是导致妊娠 22 至 28 周之间出生婴儿死亡的主要原因。阐明了贫血与 NEC 之间的联系，特别是“肠漏”表现，其特征是巨噬细胞浸润、红细胞输注相关的浸润巨噬细胞激活，以及由此产生的结果我们的长期目标是研究贫血引起的免疫变化。我们使用红细胞输注过程中的新生儿肝脏及其对肠粘膜损伤的贡献。我们现有的临床前贫血小鼠模型表明，贫血与招募表达触发性骨髓受体 1 (trem1) 的独特单核细胞群 (CD11bhiF4/80midLy6Cmid)，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。由此，新生儿贫血肝单核细胞对血红素（在储存的红细胞）比骨髓来源的细胞更能抑制这种炎症反应。抗trem1抗体治疗或通过沉默单核细胞trem1表达综合起来，研究人员发现。提出了一个新的假设，即在贫血的情况下，肠-肝-肠回旋效应被称为渗漏贫血期间肠道和相关细菌易位通过门静脉传播到肝脏，触发原位发展的肝白细胞群扩大，并继续渗透贫血肠道，为了检验我们的中心假设，我们将进行以下具体研究。目标：目标 1：阐明贫血期间招募到新生儿肠道的巨噬细胞的个体发育。定义 trem1 信号传导对肝单核细胞迁移至贫血肠道的作用，以及对红细胞输注过程中的炎症激活目标 3：确定治疗是否靶向肝脏。贫血期间的 trem1+ 单核细胞可以预防/减轻红细胞输注相关的 NEC 样损伤。实现所提出的目标将开发出一种有效的抑制肝功能的治疗策略。贫血期间的反应而不抑制保护性先天免疫机制。