Miyake Hiromu, Seo Shogo, Fujiwara Naho, Miyahara Katsumi, Lee Carol, Li Bo, Chen Yong, Yamataka Atsuyuki, Pierro Agostino
Division of General and Thoracic Surgery, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G1X8, Canada.
Department of Pediatric Surgery, Shizuoka Children's Hospital, 860 Urushiyama, Aoi-ku, Shizuoka, 4208660, Japan.
Pediatr Surg Int. 2019 Dec;35(12):1339-1343. doi: 10.1007/s00383-019-04559-1. Epub 2019 Sep 25.
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.
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.
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.
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.
坏死性小肠结肠炎（NEC）是婴儿期最严重的胃肠道疾病之一。缺氧是已知的NEC发生的主要危险因素之一。内皮素已知可调节血管收缩，有两种受体（A和B）。然而，内皮素受体B（EDNRB）在新生儿肠道损伤中的作用仍不清楚。我们旨在研究EDNRB是否参与NEC的病理生理过程。
在获得伦理批准（#44032）后，对EDNRB杂合敲除小鼠幼崽（EDNRB±）及其野生型（WT）同窝小鼠进行研究。从出生后第5天至第9天（P5 - P9）通过缺氧、灌喂配方奶和给予脂多糖诱导NEC。在P9时，采集回肠。
WT小鼠诱导NEC与黏膜损伤有关。然而，EDNRB±NEC小鼠的黏膜损伤减轻。同样，与WT NEC小鼠相比，EDNRB±小鼠的IL - 6 mRNA表达显著降低。与WT NEC相比，EDNRB±小鼠的匹莫硝唑免疫染色也显著降低，提示组织缺氧减轻。
EDNRB的部分敲除导致NEC严重程度降低和组织缺氧减轻。肠道灌注和缺氧是NEC发病机制的重要因素。这些发现与理解NEC的病理生理学以及开发NEC的新型预防策略相关。
