Hiromu Miyake1,2, Shogo Seo1,3, Naho Fujiwara3, Katsumi Miyahara3, Carol Lee1, Bo Li1, Yong Chen4, Atsuyuki Yamataka3, Agostino Pierro5. 1. Division of General and Thoracic Surgery, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G1X8, Canada. 2. Department of Pediatric Surgery, Shizuoka Children's Hospital, 860 Urushiyama, Aoi-ku, Shizuoka, 4208660, Japan. 3. Department of Pediatric General and Urogenital Surgery, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. 4. Department of Pediatric Surgery, KK Women's and Children's Hospital, 100 Bukit Timah Road, Singapore, 229899, Singapore. 5. Division of General and Thoracic Surgery, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G1X8, Canada. agostino.pierro@sickkids.ca.
Abstract
BACKGROUND: Necrotizing enterocolitis (NEC) is one of the most severe gastrointestinal diseases in infancy. Hypoxia is known as one of the major risk factors for the development of NEC. Endothelin, known to regulate vasoconstriction, has two receptors (A and B). However, the role of endothelin receptor B (EDNRB) in neonatal intestinal injury remains unclear. We aimed to investigate whether EDNRB is involved in NEC pathophysiology. METHODS: Following ethical approval (#44032), EDNRB hetero knockout mice pups (EDNRB±) and their wild-type (WT) littermates were studied. NEC was induced from postnatal day 5-9 (P5-P9) by hypoxia, gavage feeding of formula and administration of lipopolysaccharide. On P9, the ileum was harvested. RESULTS: NEC induction in WT mice was associated with mucosal injury. However, EDNRB± NEC mice had reduced mucosal injury. Similarly, EDNRB± mice had significantly lower expression of IL-6 mRNA compared to WT NEC mice. Pimonidazole immunostaining was also significantly lower in EDNRB± compared to WT NEC, suggesting reduced tissue hypoxia. CONCLUSIONS: Partial knockout of EDNRB results in reduced NEC severity and reduced tissue hypoxia. Intestinal perfusion and hypoxia are important elements of NEC pathogenesis. These findings are relevant to the understanding of NEC pathophysiology and to the development of novel preventive strategies for NEC.
BACKGROUND:Necrotizing enterocolitis (NEC) is one of the most severe gastrointestinal diseases in infancy. Hypoxia is known as one of the major risk factors for the development of NEC. Endothelin, known to regulate vasoconstriction, has two receptors (A and B). However, the role of endothelin receptor B (EDNRB) in neonatal intestinal injury remains unclear. We aimed to investigate whether EDNRB is involved in NEC pathophysiology. METHODS: Following ethical approval (#44032), EDNRB hetero knockout mice pups (EDNRB±) and their wild-type (WT) littermates were studied. NEC was induced from postnatal day 5-9 (P5-P9) by hypoxia, gavage feeding of formula and administration of lipopolysaccharide. On P9, the ileum was harvested. RESULTS:NEC induction in WT mice was associated with mucosal injury. However, EDNRB± NECmice had reduced mucosal injury. Similarly, EDNRB± mice had significantly lower expression of IL-6 mRNA compared to WT NECmice. Pimonidazole immunostaining was also significantly lower in EDNRB± compared to WT NEC, suggesting reduced tissue hypoxia. CONCLUSIONS: Partial knockout of EDNRB results in reduced NEC severity and reduced tissue hypoxia. Intestinal perfusion and hypoxia are important elements of NEC pathogenesis. These findings are relevant to the understanding of NEC pathophysiology and to the development of novel preventive strategies for NEC.
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