Red Cell Transfusion-associated Necrotizing Enterocolitis in Premature Infants

描述（由申请方提供）：坏死性小肠结肠炎（NEC）是早产儿的一种炎性肠坏死，是妊娠32周前出生或出生体重小于1500 g的婴儿发病和死亡的主要原因。近年来，一些回顾性研究表明，25-40%的NEC病例发生在接受红细胞（RBC）输注后48小时内。由于大多数早产儿在妊娠32周之前出生，在住院期间需要一次或多次RBC输注，因此有必要对这种相关性进行严格评估，以改善临床实践并制定治疗策略以预防/改善这种情况。为了研究RBC输注相关的NEC，研究人员开发了一种新的小鼠模型，其中10天大的小鼠幼崽接受静脉内RBC输注，并观察长达48小时。基于初步数据，研究人员提出了一个新的假设，即输血相关的NEC发生在早产儿中，因为RBC输血激活了贫血新生儿肠道中存在的发育调节的炎性中性粒细胞亚群，导致炎症性肠道粘膜损伤。有三个具体目标：（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性损伤的机制;（2）确定输血相关的新生儿肠道损伤是否与输血前贫血的严重程度增加和输注的红细胞储存时间延长有关;以及（3）确定在输血前洗涤或照射RBC是否可以改变输血诱导的新生儿肠损伤的严重程度。实现提出的目标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NEC的机制和潜在策略，表征新生儿RBC输注的免疫调节/炎症作用，确定RBC储存对输血相关不良事件的影响，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。

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.