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; 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），这是一种炎症性肠坏死，其特征是 巨噬细胞前体（S），以及在22岁和28周之间出生的人死亡的主要原因。 我们最近阐明了贫血与NEC之间的联系，特别是“肠道渗漏”的表现 以单核细胞浸润，RBC输血相关的激活为特征 导致肠粘膜损伤。我们的长期目标是研究贫血引起的免疫力变化 新生儿肝脏及其对RBC输血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鼠模型的贫血模型表明，贫血与肠道有关 募集独特的单核细胞（CD11BHILY6CMID）触发髓样受体1 （TREM1），类似于新生儿肝脏中发生的单核细胞，但与骨髓或sleen中的单核细胞不同。 与此相一致，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 在储存的rbc中）比骨row衍生的细胞。这种炎症反应可能会被 使用抗Trem1抗体处理或通过沉默单核细胞TREM1表达。总的来说， 研究人员提出了一个新的假设，即在贫血的环境中，肠肝脏旋转的效果采用 将贫血期间的肠道肠道和相关细菌易位作为通过门静脉传达到 肝脏触发肝白细胞种群的膨胀，原位发展为渗透 麻醉肠道肠，易于加入RBC相关的肠道损伤。为了检验我们的中心假设，我们将追求 以下具体目的：目标1：阐明在新生儿肠道中募集的单核细胞的个体发育 贫血。 AIM 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， 以及RBC输血期间的炎症激活。目标3：确定是否热靶向 贫血期间的肝脏TREM1+单核细胞可以预防/减弱RBC-输血相关的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。