在小鼠实验性坏死性小肠结肠炎模型中，硫化氢可提供肠道保护。

Hydrogen sulfide provides intestinal protection during a murine model of experimental necrotizing enterocolitis.

作者信息

Drucker Natalie A, Jensen Amanda R, Ferkowicz Michael, Markel Troy A

机构信息

Department of Surgery, Section of Pediatric Surgery, Indianapolis, IN; The Indiana University School of Medicine, Indianapolis, IN.

Department of Surgery, Section of Pediatric Surgery, Indianapolis, IN; Riley Hospital for Children at Indiana University Health, Indianapolis, IN; The Indiana University School of Medicine, Indianapolis, IN.

出版信息

J Pediatr Surg. 2018 Sep;53(9):1692-1698. doi: 10.1016/j.jpedsurg.2017.12.003. Epub 2017 Dec 24.

DOI:10.1016/j.jpedsurg.2017.12.003

PMID:29338840

Abstract

BACKGROUND

Necrotizing enterocolitis (NEC) continues to be a morbid surgical condition among preterm infants. Novel therapies for this condition are desperately needed. Hydrogen sulfide (HS) is an endogenous gasotransmitter that has been found to have beneficial properties. We therefore hypothesized that intraperitoneal injection of various HS donors would improve clinical outcomes, increase intestinal perfusion, and reduce intestinal injury in an experimental mouse model of necrotizing enterocolitis.

METHODS

NEC was induced in five-day-old mouse C57BL/6 mouse pups through maternal separation, formula feeding, and intermittent hypoxic and hypothermic stress. The control group (n=10) remained with their mother and breastfed ad lib. Experimental groups (n=10/group) received intraperitoneal injections of phosphate buffered saline (PBS) vehicle or one of the following HS donors: (1) GYY4137, 50mg/kg daily; (2) Sodium sulfide (NaS), 20mg/kg three times daily; (3) AP39, 0.16mg/kg daily. Pups were monitored for weight gain, clinical status, and intestinal perfusion via transcutaneous Laser Doppler Imaging (LDI). After sacrifice on day nine, intestinal appearance and histology were scored and cytokines were measured in tissue homogenates of intestine, liver, and lung. Data were compared with Mann-Whitney and p<0.05 was considered significant.

RESULTS

Clinical score and weight gain were significantly improved in all three HS-treated groups as compared to vehicle (p<0.05 for all groups). Intestinal perfusion of the vehicle group was 22% of baseline while the GYY4137 group was 38.7% (p=0.0103), NaS was 47.0% (p=0.0040), and AP39 was 43.0% (p=0.0018). The vehicle group had a median histology score of 2.5, while the GYY4137 group's was 1 (p=0.0013), NaS was 0.5 (p=0.0004), and AP39 was 0.5 (p=0.0001). Cytokine analysis of the intestine of the HS-treated groups revealed levels closer to breastfed pups as compared to vehicle (p<0.05 for all groups).

CONCLUSION

Intraperitoneal administration of HS protects against development of NEC by improving mesenteric perfusion, and by limiting mucosal injury and altering the tissue inflammatory response. Further experimentation is necessary to elucidate downstream mechanisms prior to clinical implementation.

摘要

背景

坏死性小肠结肠炎（NEC）仍是早产儿中一种严重的外科疾病。迫切需要针对这种疾病的新疗法。硫化氢（HS）是一种内源性气体信号分子，已被发现具有有益特性。因此，我们假设在坏死性小肠结肠炎实验小鼠模型中，腹腔注射各种HS供体将改善临床结局、增加肠道灌注并减少肠道损伤。

方法

通过母体分离、配方奶喂养以及间歇性低氧和低温应激，在5日龄C57BL/6小鼠幼崽中诱导NEC。对照组（n = 10）与母亲在一起并随意母乳喂养。实验组（每组n = 10）腹腔注射磷酸盐缓冲盐水（PBS）载体或以下HS供体之一：（1）GYY4137，每日50mg/kg；（2）硫化钠（NaS），每日20mg/kg，分三次注射；（3）AP39，每日0.16mg/kg。通过经皮激光多普勒成像（LDI）监测幼崽的体重增加、临床状态和肠道灌注。在第9天处死动物后，对肠道外观和组织学进行评分，并在肠、肝和肺的组织匀浆中测量细胞因子。数据采用Mann-Whitney检验进行比较，p<0.05被认为具有统计学意义。

结果

与载体组相比，所有三个HS治疗组的临床评分和体重增加均显著改善（所有组p<0.05）。载体组的肠道灌注为基线的22%，而GYY4137组为38.7%（p = 0.0103），NaS组为47.0%（p = 0.0040），AP39组为43.0%（p = 0.0018）。载体组的组织学评分中位数为2.5，而GYY4137组为1（p = 0.0013），NaS组为0.5（p = 0.0004），AP39组为0.5（p = 0.0001）。HS治疗组肠道的细胞因子分析显示，与载体组相比，其水平更接近母乳喂养的幼崽（所有组p<0.05）。