Journal of cellular and molecular medicine

1582-493425232021DecJournal of cellular and molecular medicineJ Cell Mol MedNeutrophil extracellular trap inhibition increases inflammation, bacteraemia and mortality in murine necrotizing enterocolitis.108141082410814-1082410.1111/jcmm.15338Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease affecting primarily premature infants. The disease is characterized by intestinal inflammation and leucocyte infiltration, often progressing to necrosis, perforation, systemic inflammatory response and death. Neutrophil extracellular traps (NETs), denoting nuclear DNA, histone and antimicrobial protein release, have been suggested to play a role in NEC. This study aimed to determine the role of NETs in NEC and explore the effect of chloramidine, a NET inhibitor, on a murine NEC-like intestinal injury model. Blood and intestinal tissues were collected from infants diagnosed with ≥ Stage II NEC, and levels of nucleosomes and NETs, respectively, were compared with those of case-matched controls. In mice, NEC was induced with dithizone/Klebsiella, and mice in the treatment group received 40 mg/kg chloramidine. Bacterial load, intestinal histology, plasma myeloperoxidase and cytokine levels, and immunofluorescent staining were compared with controls. Nucleosomes were significantly elevated in both human and mouse NEC plasma, whereas NET staining was only present in NEC tissue in both species. Chloramidine treatment increased systemic inflammation, bacterial load, organ injury and mortality in murine NEC. Taken together, our findings suggest that NETs are critical in the innate immune defence during NEC in preventing systemic bacteraemia.© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.ChaabanHalaH0000-0002-7112-564XDepartment of Pediatrics, Division of Neonatology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.BurgeKathrynK0000-0003-4128-5383Department of Pediatrics, Division of Neonatology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.EckertJeffreyJDepartment of Pediatrics, Division of Neonatology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.KeshariRavi SRS0000-0002-4177-9095Oklahoma Medical Research Foundation, Cardiovascular Biology Research Program, Oklahoma City, OK, USA.SilasiRobertROklahoma Medical Research Foundation, Cardiovascular Biology Research Program, Oklahoma City, OK, USA.LupuCristinaC0000-0001-8619-0893Oklahoma Medical Research Foundation, Cardiovascular Biology Research Program, Oklahoma City, OK, USA.WarnerBarbaraB0000-0002-9910-4461Department of Pediatrics, Division of Newborn Medicine, Washington University School of Medicine, St. Louis, MO, USA.EscobedoMarilynMDepartment of Pediatrics, Division of Neonatology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.CaplanMichaelMUniversity of Chicago Pritzker School of Medicine, Chicago, IL, USA.LupuFloreaF0000-0003-1249-9278Oklahoma Medical Research Foundation, Cardiovascular Biology Research Program, Oklahoma City, OK, USA.engR01 GM121601GMNIGMS NIH HHSUnited StatesK08 GM127308GMNIGMS NIH HHSUnited StatesP30 GM114731GMNIGMS NIH HHSUnited StatesP30GM114731GMNIGMS NIH HHSUnited StatesGM121601GMNIGMS NIH HHSUnited StatesK08GM127308GMNIGMS NIH HHSUnited StatesGM122775GMNIGMS NIH HHSUnited StatesJournal ArticleObservational StudyResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov't20200608