Red Cell Transfusion-associated Necrotizing Enterocolitis in Premature Infants

早产儿红细胞输注相关的坏死性小肠结肠炎

• 批准号: 9099903
• 负责人: Akhil Maheshwari
• 金额: $ 38.07万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9099903
• 关键词: Address; Adult; Adverse event; Affect; Age; Anemia; Animal Model; Animals; Birth Weight; Blood Transfusion; Clinical; Clinical Research; Control Animal; Data; Erythrocyte Transfusion; Erythrocytes; Evaluation; Funding Opportunities; Genes; Health; Hematocrit procedure; Hemorrhage; Hour; Human; Infant; Inflammation; Inflammatory; Injury; Intestines; Intravenous; Length of Stay; Lipopolysaccharides; Molecular; Morbidity - disease rate; Mus; Necrosis; Necrotizing Enterocolitis; Neonatal; Neutrophil Infiltration; Phenotype; Population; Pregnancy; Premature Infant; Process; Research Personnel; Retrospective Studies; Risk; Severities; TNF gene; Therapeutic; Toll-like receptors; Transfusion; Up-Regulation; Venous blood sampling; base; clinical practice; improved; irradiation; mortality; mouse model; neonate; neutrophil; novel; premature; premature neonates; prevent; prophylactic; pup

DESCRIPTION (provided by applicant): Necrotizing enterocolitis (NEC), an inflammatory bowel necrosis of premature infants, is a leading cause of morbidity and mortality in infants born prior to 32 weeks of gestation or with a birth weight less than 1500 g. In recent years, several retrospective studies have shown that 25-40% of all cases of NEC occurred within 48h of receiving a red blood cell (RBC) transfusion. Because most premature infants born prior to 32 weeks' gestation will require one or more RBC transfusions during hospital stay, critical evaluation of this association is necessary to improve clinical practice and develop therapeutic strategies to prevent/ameliorate this condition. To investigate RBC transfusion-associated NEC, the investigators have developed a novel murine model where 10-day-old mouse pups receive an intravenous RBC transfusion and are observed for up to 48h. Based on preliminary data, the investigators propose a novel hypothesis that transfusion-associated NEC occurs in premature neonates because RBC transfusions activate a developmentally-regulated, inflammatory subpopulation of neutrophils present in the anemic neonatal intestine, which cause inflammatory gut mucosal injury. There are three specific aims: (1) Elucidate the mechanism(s) by which severe anemia and subsequent RBC transfusions induce neutrophil infiltration and cause inflammatory injury in the neonatal intestine; (2) Determine whether transfusion-associated neonatal intestinal injury worsens with increasing severity of pre-transfusion anemia and longer storage age of transfused RBCs; and (3) Determine whether washing or irradiation of RBCs prior to transfusion can alter the severity of transfusion-induced neonatal intestinal injury. Accomplishment of the proposed aims will develop an effective animal model to study the mechanisms and potential strategies to prevent/treat transfusion-associated NEC in neonates, characterize the immunomodulatory/inflammatory effects of RBC transfusions in neonates, define the effect of RBC storage on a transfusion-associated adverse event, and appraise prophylactic vs. therapeutic transfusion strategies in premature infants with anemia of prematurity.

描述（由申请人提供）：坏死性小肠结肠炎（NEC）是一种早产儿炎症性肠坏死，是妊娠 32 周之前出生或出生体重低于 1500 克的婴儿发病和死亡的主要原因。近年来，多项回顾性研究表明，所有 NEC 病例中有 25-40% 发生在接受红细胞 (RBC) 输注后 48 小时内。由于大多数妊娠 32 周之前出生的早产儿在住院期间需要一次或多次红细胞输注，因此有必要对这种关联进行严格评估，以改善临床实践并制定预防/改善这种情况的治疗策略。为了研究红细胞输注相关的 NEC，研究人员开发了一种新型小鼠模型，其中 10 日龄的幼鼠接受静脉红细胞输注，并观察长达 48 小时。根据初步数据，研究人员提出了一个新的假设，即早产儿发生输血相关的 NEC 是因为红细胞输注激活了贫血新生儿肠道中发育调节的炎症性中性粒细胞亚群，从而导致炎症性肠粘膜损伤。其具体目标有3个：（1）阐明严重贫血和随后的红细胞输注诱导中性粒细胞浸润并引起新生儿肠道炎症损伤的机制； (2)确定输血相关的新生儿肠道损伤是否随着输血前贫血严重程度的增加和输注红细胞储存时间的延长而加重； (3) 确定输血前红细胞的洗涤或照射是否可以改变输血引起的新生儿肠道损伤的严重程度。实现所提出的目标将开发一种有效的动物模型来研究预防/治疗新生儿输血相关 NEC 的机制和潜在策略，表征新生儿红细胞输注的免疫调节/炎症作用，定义红细胞储存对输血的影响相关的不良事件，并评估患有早产儿贫血的早产儿的预防性与治疗性输血策略。