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Abstract
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.
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1 Department of Pediatrics, Morsani College of Medicine, University of South Florida, Tampa, FL, USA; Department of Pediatrics, Johns Hopkins University, Baltimore, MD, USA
2 Department of Pediatrics, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
3 Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
4 Department of Comparative Medicine, University of South Florida, Tampa, FL, USA; Center for Comparative Medicine, Massachusetts General Hospital, Boston, MA, USA
5 Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA; Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA
6 Department of Cardiology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
7 Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA
8 Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
9 Department of Pediatrics, Johns Hopkins University, Baltimore, MD, USA