Department of Surgery, Indiana University School of Medicine, Riley Hospital for Children, 705 Riley Hospital Drive, RI 2500, Indianapolis, IN 46202, USA.
Department of Surgery, Indiana University School of Medicine, Riley Hospital for Children, 705 Riley Hospital Drive, RI 2500, Indianapolis, IN 46202, USA.
J Pediatr Surg. 2022 Dec;57(12):967-973. doi: 10.1016/j.jpedsurg.2022.06.001. Epub 2022 Jun 9.
Necrotizing enterocolitis (NEC) is a devastating disease that impacts the intestine of premature infants. Sildenafil has shown benefit in colitis and ischemia/reperfusion models but has not been adequately studied in NEC. Sildenafil's best studied mechanism involves augmenting nitric oxide induced vasodilation. We hypothesized that sildenafil would improve outcomes during experimental NEC in an eNOS dependent manner.
NEC was induced in five-day old mouse pups with gavage formula feeds plus intermittent hypoxia and hypothermia. Using wild type (WT) mice, the route of sildenafil administration was studied in the following groups: (1) breastfed controls, (2) NEC + oral (PO) sildenafil, (3) NEC + PO vehicle, (4) NEC + intraperitoneal (IP) sildenafil, (5) NEC + IP vehicle. The eNOS KO groups studied included: (1) breastfed controls, (2) NEC + PO sildenafil, (3) NEC + PO vehicle. Data were tested for normality and compared using t-tests or Mann-Whitney with a p-value <0.05 considered significant.
In WT mice, oral and IP sildenafil resulted in improved clinical outcomes compared to their respective vehicle group. Only orally administered sildenafil significantly improved perfusion to the intestine and protected it from macroscopic and histologic injury. When repeated in eNOS KO mice, oral sildenafil improved clinical scores and attenuated intestinal injury scores, despite no effect on intestinal perfusion.
Sildenafil, when administered orally, improves clinical outcomes and protects the intestine in a murine model of experimental necrotizing enterocolitis. While sildenafil requires eNOS to impact mesenteric perfusion, it does not appear to be dependent on eNOS to attenuate intestinal injury.
坏死性小肠结肠炎（NEC）是一种严重影响早产儿肠道的疾病。西地那非已在结肠炎和缺血/再灌注模型中显示出益处，但在 NEC 中研究不足。西地那非最被广泛研究的机制涉及增强一氧化氮诱导的血管扩张。我们假设西地那非将以依赖 eNOS 的方式改善实验性 NEC 的结果。
通过管饲配方喂养加间歇性低氧和低体温，在 5 天大的小鼠幼仔中诱导 NEC。使用野生型（WT）小鼠，在以下组中研究了西地那非的给药途径：（1）母乳喂养对照，（2）NEC+口服（PO）西地那非，（3）NEC+PO 载体，（4）NEC+腹腔内（IP）西地那非，（5）NEC+IP 载体。研究的 eNOS KO 组包括：（1）母乳喂养对照，（2）NEC+PO 西地那非，（3）NEC+PO 载体。对数据进行正态性检验，并用 t 检验或 Mann-Whitney 检验进行比较，p 值<0.05 认为有统计学意义。
在 WT 小鼠中，与各自的载体组相比，口服和 IP 西地那非可改善临床结局。只有口服西地那非可显著改善肠道灌注并保护其免受宏观和组织学损伤。在 eNOS KO 小鼠中重复使用时，口服西地那非可改善临床评分并减轻肠道损伤评分，尽管对肠道灌注没有影响。
西地那非口服给药可改善实验性坏死性小肠结肠炎小鼠模型的临床结局并保护肠道。虽然西地那非需要 eNOS 来影响肠系膜灌注，但它似乎不依赖于 eNOS 来减轻肠道损伤。
