Red Cell Transfusion-associated Necrotizing Enterocolitis in Premature Infants

描述(申请人提供)：坏死性小肠结肠炎(NEC)是早产儿的一种炎症性肠道坏死，是妊娠32周前出生或出生体重低于1500克的婴儿发病率和死亡率的主要原因。近年来，几项回顾性研究表明，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。由于大多数在32周前出生的早产儿在住院期间需要一次或多次红细胞输注，因此有必要对这种相关性进行批判性评估，以改进临床实践并制定预防/改善这种情况的治疗策略。为了研究与RBC输注相关的NEC，研究人员开发了一种新的小鼠模型，10天大的小鼠接受静脉输注RBC，并进行长达48小时的观察。基于初步数据，研究人员提出了一个新的假设，即输血相关NEC发生在早产儿中，因为输血激活了贫血新生儿肠道中存在的发育调节的炎症性中性粒细胞亚群，从而导致炎症性肠黏膜损伤。有三个具体目的：(1)阐明严重贫血和随后的红细胞输注导致中性粒细胞渗入并导致新生儿肠道炎症损伤的机制(S)；(2)确定输血前贫血的严重程度和输血后红细胞的保存时间延长是否会加重输血相关的新生儿肠道损伤；以及(3)确定输血前清洗或照射红细胞是否可以改变输血引起的新生儿肠道损伤的严重程度。这些目标的实现将开发一种有效的动物模型，以研究预防/治疗新生儿输血相关性NEC的机制和可能的策略，表征新生儿输注红细胞的免疫调节/炎症效应，确定红细胞储存对输血相关不良事件的影响，并评估早产儿贫血的预防和治疗输血策略。

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.