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.
Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in premature infants. Clinical studies in recent years show that NEC occurs in a third of all cases within 48 hours of receiving a blood transfusion. In this applicatio, the investigators present a novel mouse model to investigate blood transfusion- associated NEC and propose sequential studies to investigate the mechanisms and potential strategies to prevent transfusion-associated NEC in premature infants.
|Ho, Thao T B; Groer, Maureen W; Kane, Bradley et al. (2018) Dichotomous development of the gut microbiome in preterm infants. Microbiome 6:157|
|Whitehead, Halana V; Vesoulis, Zachary A; Maheshwari, Akhil et al. (2018) Anemia of prematurity and cerebral near-infrared spectroscopy: should transfusion thresholds in preterm infants be revised? J Perinatol 38:1022-1029|
|Maheshwari, Akhil; Patel, Ravi M; Christensen, Robert D (2018) Anemia, red blood cell transfusions, and necrotizing enterocolitis. Semin Pediatr Surg 27:47-51|
|Namachivayam, Kopperuncholan; MohanKumar, Krishnan; Garg, Lalit et al. (2017) Neonatal mice with necrotizing enterocolitis-like injury develop thrombocytopenia despite increased megakaryopoiesis. Pediatr Res 81:817-824|
|MohanKumar, Krishnan; Namachivayam, Kopperuncholan; Cheng, Feng et al. (2017) Trinitrobenzene sulfonic acid-induced intestinal injury in neonatal mice activates transcriptional networks similar to those seen in human necrotizing enterocolitis. Pediatr Res 81:99-112|
|MohanKumar, Krishnan; Namachivayam, Kopperuncholan; Ho, Thao T B et al. (2017) Cytokines and growth factors in the developing intestine and during necrotizing enterocolitis. Semin Perinatol 41:52-60|
|Maheshwari, Akhil (2015) Immunologic and Hematological Abnormalities in Necrotizing Enterocolitis. Clin Perinatol 42:567-85|