A murine neonatal model of necrotizing enterocolitis caused by anemia and red blood cell transfusions

Krishnan MohanKumar, Kopperuncholan Namachivayam, Tanjing Song, Byeong Jake Cha, Andrea Slate, Jeanne E. Hendrickson, Hua Pan, Samuel A. Wickline, Joo-Yeun Oh, Rakesh P. Patel, Ling He, Benjamin A. Torres and Akhil Maheshwari ()
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Krishnan MohanKumar: University of South Florida
Kopperuncholan Namachivayam: University of South Florida
Tanjing Song: University of South Florida
Byeong Jake Cha: University of South Florida
Andrea Slate: University of South Florida
Jeanne E. Hendrickson: Yale School of Medicine
Hua Pan: University of South Florida
Samuel A. Wickline: University of South Florida
Joo-Yeun Oh: University of Alabama at Birmingham
Rakesh P. Patel: University of Alabama at Birmingham
Ling He: Johns Hopkins University
Benjamin A. Torres: University of South Florida
Akhil Maheshwari: University of South Florida

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11199-5

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