Department of Pediatrics, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, USA.
Department of Pediatrics, Johns Hopkins University, Baltimore, MD, 21287, USA.
Nat Commun. 2019 Aug 2;10(1):3494. doi: 10.1038/s41467-019-11199-5.
Necrotizing enterocolitis (NEC) is an idiopathic, inflammatory bowel necrosis of premature infants. Clinical studies have linked NEC with antecedent red blood cell (RBC) transfusions, but the underlying mechanisms are unclear. Here we report a neonatal murine model to investigate this association. C57BL/6 mouse pups rendered anemic by timed phlebotomy and then given RBC transfusions develop NEC-like intestinal injury with prominent necrosis, inflammation, and submucosal edema/separation of the lamina propria in the ileocecal region and colon within 12-24 h. The anemic intestine is infiltrated by inflammatory macrophages, which are activated in situ by RBC transfusions via a Toll-like receptor (TLR)-4-mediated mechanism and cause bowel injury. Chelation of RBC degradation products with haptoglobin, absence of TLR4, macrophage depletion, and inhibition of macrophage activation is protective. Intestinal injury worsens with increasing severity and the duration of anemia prior to transfusion, indicating a need for the re-evaluation of current transfusion guidelines for premature infants.
坏死性小肠结肠炎（NEC）是一种特发性、炎症性的早产儿肠坏死。临床研究表明 NEC 与先前的红细胞（RBC）输血有关，但潜在机制尚不清楚。在这里，我们报告了一种新生鼠模型来研究这种关联。通过定时放血使 C57BL/6 幼鼠出现贫血，然后给予 RBC 输血，在 12-24 小时内，回肠和结肠的回盲部区域会出现类似 NEC 的肠道损伤，表现为明显的坏死、炎症和黏膜下水肿/固有层分离。贫血的肠道浸润有炎症巨噬细胞，这些巨噬细胞通过 TLR-4 介导的机制在 RBC 输血时原位激活，导致肠道损伤。RBC 降解产物与触珠蛋白螯合、TLR4 缺失、巨噬细胞耗竭和巨噬细胞激活抑制具有保护作用。肠道损伤随着输血前贫血的严重程度和持续时间的增加而加重，这表明需要重新评估目前早产儿的输血指南。
