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.

项目摘要 贫血是早产儿中几乎普遍的诊断，主要由医疗必需的静脉切开术引起。 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一问题。当 严重到需要红细胞输注治疗，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），一种特征为 巨噬细胞前体，并且是妊娠22- 28周之间出生的人死亡的主要原因。 我们最近阐明了贫血和NEC之间的联系，特别是“漏肠”表现 其特征在于单核细胞浸润，RBC输注相关的浸润单核细胞活化， 导致肠粘膜损伤。我们的长期目标是研究贫血引起的免疫变化， 新生儿肝脏及其在红细胞输注期间对肠粘膜损伤的贡献。我们的初步研究 使用我们现有的贫血的临床前小鼠模型，证明贫血与肠道疾病有关。 募集表达触发型髓样受体1的单核细胞（CD 11bhiLy 6Cmid）的独特群体 （trem 1），类似于新生儿肝脏中发育的单核细胞，但不同于骨髓或脾脏中的单核细胞。 与此一致，新生儿贫血的肝单核细胞对血红素显示出更大的炎症激活（发现 在储存的RBC中）比骨髓来源的细胞更好。这种炎症反应可以被抑制， 使用抗TREM 1抗体治疗或通过沉默单核细胞TREM 1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-肠的回飞棒效应 当贫血期间肠漏和相关的细菌移位通过门静脉传播， 肝脏，触发原位发育的肝白细胞群的扩增， 贫血的肠道，易患红细胞相关的肠道损伤。为了验证我们的核心假设，我们将继续 目的1：阐明单核细胞的个体发育过程中招募到新生儿肠道 贫血目的2：确定tem 1信号在肝单核细胞迁移到贫血肠中的作用， 以及红细胞输注期间的炎症激活。目的3：确定治疗靶向是否为 在贫血期间肝Trem 1+单核细胞可以预防/减轻RBC输血相关的NEC样损伤。 所提出的目标的实现将开发一种有效的抑制肝细胞凋亡的治疗策略。 贫血期间的免疫应答，而不抑制保护性先天免疫机制。