Endothelin receptor B affects the perfusion of newborn intestine: possible mechanism of necrotizing enterocolitis development
Endothelin receptor B affects the perfusion of newborn intestine: possible mechanism of necrotizing enterocolitis development
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DOI：
10.1007/s00383-019-04559-1
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发表时间：
2019-12-01
影响因子：
1.8
通讯作者：
Pierro, Agostino
中科院分区：
文献类型：
--
作者：
Miyake, Hiromu;Seo, Shogo;Pierro, Agostino
背景 坏死性小肠结肠炎（NEC）是婴儿期最严重的胃肠道疾病之一。缺氧被认为是 NEC 发生的主要危险因素之一。已知内皮素可调节血管收缩，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。我们的目的是研究 EDNRB 是否参与 NEC 病理生理学。方法 经过伦理批准 (#44032)，对 EDNRB 杂种基因敲除小鼠幼崽 (EDNRB +/-) 及其野生型 (WT) 同窝小鼠进行了研究。从出生后第5-9天(P5-P9)开始，通过缺氧、强饲配方奶和给予脂多糖来诱导NEC。在 P9 时，收获回肠。结果 WT 小鼠中的 NEC 诱导与粘膜损伤相关。然而，EDNRB +/- NEC 小鼠的粘膜损伤减少。类似地，与 WT NEC 小鼠相比，EDNRB +/- 小鼠的 IL-6 mRNA 表达显着降低。与 WT NEC 相比，EDNRB +/- 中哌莫硝唑免疫染色也显着较低，表明组织缺氧减少。结论 部分敲除 EDNRB 可降低 NEC 严重程度并减少组织缺氧。肠道灌注和缺氧是 NEC 发病机制的重要因素。这些发现与 NEC 病理生理学的理解以及 NEC 新型预防策略的开发相关。
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.