Anemia represents one of the most common complications of preterm birth. Treatment of neonatal anemia is largely based on measured hemoglobin concentrations (Hb). As patient blood management practices have become more conservative, and neonatologists have utilized lower Hb thresholds to trigger transfusions, recent studies have raised concerns regarding the health consequences of restrictive transfusion practices. Consistent with this, our recent multicenter prospective cohort investigation demonstrated that anemia in preterm infants (Hb ?8g/dL) is associated with the development of necrotizing enterocolitis (NEC), a serious intestinal disease and major cause of death in preterm neonates. Our long-term objective is to identify key mechanisms that regulate anemia-associated gut injury and NEC. Our central hypothesis is that severe anemia induces alterations in macrophage function that directly predisposes neonates to intestinal injury and NEC. Our hypothesis is formulated on the basis of our recent discovery that anemia in preterm infants can result in impaired gut oxygenation as measured by near infrared spectroscopy (NIRS) of mesenteric regional saturation of oxygen (MES-rSO2). Anemic preterm infants can also display significant increases in serum levels of proinflammatory interferon gamma (IFN?). Using a preclinical model, our preliminary data also demonstrate that severe anemia not only induces gut hypoxia, but also drives IFN? production by intestinal macrophages. As anemia can induce hypoxia-inducible factor 1? (HIF1?) in macrophages and HIF1? can drive macrophage- production of IFN?, these results suggest that anemia-induced changes in gut oxygenation drive HIF1?- induced IFN? production by intestinal macrophages. Furthermore, as our preliminary data demonstrate that anemia induces intestinal injury and previous studies demonstrate that IFN? can directly compromise epithelial barrier function, anemia-induced production of IFN? by macrophages may directly compromise the integrity of the gut mucosa in addition to driving a positive feedback loop of additional proinflammatory monocyte and macrophage differentiation, macrophage IFN? production, barrier dysfunction, intestinal injury and ultimately NEC. To test our central hypothesis and therefore accomplish the overall objectives of Project 2, we will pursue the following specific aims:
Aim 1 : Define the impact of anemia and its treatment (RBC transfusion) on serum cytokines and monocyte differentiation in pre-term infants.
Aim 2 : Define the impact of anemia and its treatment (RBC transfusion or recombinant human erythropoietin (rHuEPO) administration) on gut macrophage cytokine secretion and intestinal injury using a preclinical model. We think these parallel aims provide a unique opportunity to define the impact of anemia on intestinal injury and NEC and therefore will help inform future validation studies and trials designed to optimally manage neonatal anemia.

Public Health Relevance

While anemia represents one of the most common complications of preterm birth, recent data suggest that severe anemia (Hb ?8g/dL) can directly predispose preterm neonates to necrotizing enterocolitis (NEC), a serious intestinal disease and major cause of death in preterm neonates. Unfortunately, the mechanisms responsible for anemia-associated NEC remain unknown. The proposed studies will use a combination of clinical and preclinical approaches to elucidate key factors responsible for anemia-associated NEC in an effort to reduce or eliminate the devastating consequences of this disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL046925-23
Application #
9968344
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Mondoro, Traci
Project Start
Project End
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
23
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Boston Children's Hospital
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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Wallin, Diana J; Zamora, Tara G; Alexander, Michelle et al. (2017) Neonatal mouse hippocampus: phlebotomy-induced anemia diminishes and treatment with erythropoietin partially rescues mammalian target of rapamycin signaling. Pediatr Res 82:501-508

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