Anemia induces gut inflammation and injury in an animal model of preterm infants

Connie M Arthur; Demet Nalbant; Henry A Feldman; Bejan J Saeedi; Jason Matthews; Brian S Robinson; Nourine A Kamili; Ashley Bennett; Gretchen A Cress; Martha Sola-Visner; Rheinallt M Jones; M Bridget Zimmerman; Andrew S Neish; Ravi M Patel; Peggy Nopoulos; Michael K Georgieff; John D Roback; John A Widness; Cassandra D Josephson; Sean R Stowell

doi:10.1111/trf.15254

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Anemia induces gut inflammation and injury in an animal model of preterm infants

Journal article

Open access

Peer reviewed

Anemia induces gut inflammation and injury in an animal model of preterm infants

Connie M Arthur, Demet Nalbant, Henry A Feldman, Bejan J Saeedi, Jason Matthews, Brian S Robinson, Nourine A Kamili, Ashley Bennett, Gretchen A Cress, Martha Sola-Visner, …

Transfusion (Philadelphia, Pa.), Vol.59(4), pp.1233-1245

04/2019

DOI: 10.1111/trf.15254

PMCID: PMC6525338

PMID: 30897226

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Abstract

While very low birth weight (VLBW) infants often require multiple red blood cell transfusions, efforts to minimize transfusion-associated risks have resulted in more restrictive neonatal transfusion practices. However, whether restrictive transfusion strategies limit transfusions without increasing morbidity and mortality in this population remains unclear. Recent epidemiologic studies suggest that severe anemia may be an important risk factor for the development of necrotizing enterocolitis (NEC). However, the mechanism whereby anemia may lead to NEC remains unknown. The potential impact of anemia on neonatal inflammation and intestinal barrier disruption, two well-characterized predisposing features of NEC, was defined by correlation of hemoglobin values to cytokine levels in premature infants and by direct evaluation of intestinal hypoxia, inflammation and gut barrier disruption using a pre-clinical neonatal murine model of phlebotomy-induced anemia (PIA). Increasing severity of anemia in the preterm infant correlated with the level of IFN-gamma, a key pro-inflammatory cytokine that may predispose an infant to NEC. Gradual induction of PIA in a pre-clinical model resulted in significant hypoxia throughout the intestinal mucosa, including areas where intestinal macrophages reside. PIA-induced hypoxia significantly increased macrophage pro-inflammatory cytokine levels, while reducing tight junction protein ZO-1 expression and increasing intestinal barrier permeability. Macrophage depletion reversed the impact of anemia on intestinal ZO-1 expression and barrier function. Taken together, these results suggest that anemia can increase intestinal inflammation and barrier disruption likely through altered macrophage function, leading to the type of predisposing intestinal injury that may increase the risk for NEC.

Inflammation - pathology

Intestinal Mucosa - metabolism

Infant, Premature, Diseases

Infant, Very Low Birth Weight

Enterocolitis, Necrotizing - metabolism

Humans

Anemia - pathology

Male

Interferon-gamma - metabolism

Inflammation - etiology

Anemia - metabolism

Anemia - complications

Inflammation - metabolism

Animals

Enterocolitis, Necrotizing - etiology

Infant, Premature

Female

Mice

Zonula Occludens-1 Protein - metabolism

Enterocolitis, Necrotizing - pathology

Infant, Newborn

Disease Models, Animal

Intestinal Mucosa - pathology

Details

Title: Subtitle: Anemia induces gut inflammation and injury in an animal model of preterm infants
Creators: Connie M Arthur - Departments of Pathology and Laboratory Medicine, Center for Transfusion and Cellular Therapies, Atlanta, Georgia
Demet Nalbant - Department of Pediatrics, University of Iowa, Iowa City, Iowa
Henry A Feldman - Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts
Bejan J Saeedi - Departments of Pathology and Laboratory Medicine, Center for Transfusion and Cellular Therapies, Atlanta, Georgia
Jason Matthews - Departments of Pathology and Laboratory Medicine, Center for Transfusion and Cellular Therapies, Atlanta, Georgia
Brian S Robinson - Departments of Pathology and Laboratory Medicine, Center for Transfusion and Cellular Therapies, Atlanta, Georgia
Nourine A Kamili - Departments of Pathology and Laboratory Medicine, Center for Transfusion and Cellular Therapies, Atlanta, Georgia
Ashley Bennett - Departments of Pathology and Laboratory Medicine, Center for Transfusion and Cellular Therapies, Atlanta, Georgia
Gretchen A Cress - Department of Pediatrics, University of Iowa, Iowa City, Iowa
Martha Sola-Visner - Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts
Rheinallt M Jones - Departments of Pathology and Laboratory Medicine, Center for Transfusion and Cellular Therapies, Atlanta, Georgia
M Bridget Zimmerman - Department of Pediatrics, University of Iowa, Iowa City, Iowa
Andrew S Neish - Departments of Pathology and Laboratory Medicine, Center for Transfusion and Cellular Therapies, Atlanta, Georgia
Ravi M Patel - Pediatrics, Emory University School of Medicine, Atlanta, Georgia
Peggy Nopoulos - Department of Psychiatry, College of Medicine, University of Iowa, Iowa City, Iowa
Michael K Georgieff - Department of Pediatrics, School of Medicine, University of Minnesota, Minneapolis, Minnesota
John D Roback - Departments of Pathology and Laboratory Medicine, Center for Transfusion and Cellular Therapies, Atlanta, Georgia
John A Widness - Department of Pediatrics, University of Iowa, Iowa City, Iowa
Cassandra D Josephson - Pediatrics, Emory University School of Medicine, Atlanta, Georgia
Sean R Stowell - Departments of Pathology and Laboratory Medicine, Center for Transfusion and Cellular Therapies, Atlanta, Georgia
Resource Type: Journal article
Publication Details: Transfusion (Philadelphia, Pa.), Vol.59(4), pp.1233-1245
DOI: 10.1111/trf.15254
PMID: 30897226
PMCID: PMC6525338
NLM abbreviation: Transfusion
ISSN: 1537-2995
eISSN: 1537-2995
Publisher: United States
Grant note: P01 HL046925 / NHLBI NIH HHS R01 HL135575 / NHLBI NIH HHS DP5OD019892 / NIH HHS DP5 OD019892 / NIH HHS R01HL13557501 / NHLBI NIH HHS P01HL04692520 / NHLBI NIH HHS
Language: English
Date published: 04/2019
Academic Unit: Neurology; Psychiatry; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Biostatistics; Gastroenterology, Hepatology, Pancreatology, and Nutrition
Record Identifier: 9984003432502771

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