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

• 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
• 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

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加剧了这种情况。什么时候 严重到需要通过红细胞输血治疗，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)，一种以巨噬细胞为特征的炎症性肠坏死 渗透，是妊娠 22 至 28 周之间出生婴儿死亡的主要原因。我们最近有 阐明了贫血与 NEC 之间的联系，特别是“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 肠粘膜损伤。我们的长期目标是研究贫血引起的免疫变化 新生儿肝脏及其对红细胞输注期间肠粘膜损伤的贡献。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类似，但与骨髓或脾中的单核细胞不同。持续的 由此，新生儿贫血肝单核细胞对血红素表现出更大的炎症激活（在储存的 红细胞）比骨髓来源的细胞更重要。这种炎症反应可以通过使用 抗trem1抗体治疗或通过沉默单核细胞trem1表达。综合来看，调查人员 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， 易发生红细胞相关肠道损伤。为了检验我们的中心假设，我们将追求以下具体内容 目的： 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。目标 2： 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 红细胞输注期间的炎症激活。目标 3：确定治疗靶点是否为肝脏 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损伤的治疗策略。 贫血期间的反应而不抑制保护性先天免疫机制。