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: 10583807
• 负责人: Mohan Kumar Krishnan
• 金额: --
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10583807
• 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; Fetus; Growth; Gut Mucosa; Hematopoiesis; Heme; Hepatic; Human; ITGAM gene; Immunity; In Situ; Infiltration; Inflammatory; Inflammatory Response; Injury; Intervention; Intestinal Mucosa; Intestinal permeability; Intestines; Investigation; 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; Sampling; Signal Transduction; Site; Source; Spleen; Surface; Testing; Transact; Transfusion; Venous blood sampling; fetal; gut-liver axis; inducible Cre; inhibitor; innate immune mechanisms; intestinal hypoxia; intestinal injury; 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 infiltration of macrophage precursor(s), 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 monocytic infiltration, RBC transfusion-associated activation of infiltrated monocytes, 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 intestinal recruitment of a unique population of monocytes (CD11bhiLy6Cmid) 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 takes place as the leaky gut and associated bacterial translocation during anemia communicate via the portal vein to the liver, triggering 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 monocytes 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 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），一种炎症性肠坏死，其特征是肠壁浸润 巨噬细胞前体，是妊娠 22 至 28 周之间出生的婴儿死亡的主要原因。 我们最近阐明了贫血与 NEC 之间的联系，特别是“肠漏”表现 其特征是单核细胞浸润、红细胞输注相关的浸润单核细胞激活以及 我们的长期目标是研究贫血引起的免疫变化。 我们的初步研究对新生儿肝脏及其对红细胞输注期间肠粘膜损伤的影响进行了研究。 使用我们现有的临床前贫血小鼠模型证明贫血与肠道有关 招募表达触发骨髓受体 1 的独特单核细胞群 (CD11bhiLy6Cmid) (trem1)，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。 与此一致的是，新生儿贫血肝单核细胞对血红素表现出更大的炎症激活（发现 储存的红细胞中）比骨髓来源的细胞更能抑制这种炎症反应。 使用抗trem1抗体治疗或通过沉默单核细胞trem1表达综合起来， 研究人员提出了一个新的假设，即在贫血的情况下，肠-肝-肠回旋效应会发生 贫血症通过门静脉传播期间，肠漏和相关细菌易位 肝脏，引发原位发展的肝白细胞群的扩张，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，我们将继续研究。 具体目标如下： 目标 1：阐明在新生儿肠道中募集的单核细胞的个体发育 目标 2：确定 trem1 信号传导对肝单核细胞迁移至贫血肠道的作用。 目标 3：确定治疗目标是否为红细胞输注过程中的炎症激活。 贫血期间的肝 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。