Table_3_Supplemental Insulin-Like Growth Factor-1 and Necrotizing Enterocolitis in Preterm Pigs.pdf

Background: Recombinant human IGF-1/binding protein-3 (rhIGF-1/BP-3) is currently tested as a therapy in preterm infants but possible effects on the gut, including necrotizing enterocolitis (NEC), have not been tested. The aim of this study was to evaluate if rhIGF-1/BP-3 supplementation in the first days after birth negatively affects clinical variables like growth, physical activity, blood chemistry and hematology and gut maturation (e.g., intestinal permeability, morphology, enzyme activities, cytokine levels, enterocyte proliferation, NEC lesions), using NEC-sensitive preterm pigs as a model for preterm infants.Methods: Preterm pigs were given twice daily subcutaneous injections of rhIGF-1/BP-3 or vehicle. Blood was collected for IGF-1 measurements and gut tissue for NEC evaluation and biochemical analyses on day 5.Results: Baseline circulating IGF-1 levels were low in preterm pigs compared with near-term pigs reared by their mother (40 ng/mL). rhIGF-1/BP-3 treatment reduced the incidence of severe NEC lesions (7/24 vs.16/24, p = 0.01) and overall NEC severity (1.8 ± 0.2 vs. 2.6 ± 0.3, p < 0.05, with most lesions occurring in colon). In the small intestine, villi length (405 ± 25 vs. 345 ± 33 μm) and activities of the brush border peptidases aminopeptidase N and dipeptidylpeptidase IV were increased in rhIGF-1/BP-3 treated pigs, relative to control pigs (+31–44%, both p < 0.05). The treatment had no effects on body weight, blood chemistry or hematology, except for an increase in blood leucocyte and neutrophil counts (p < 0.05, i.e., reduced neonatal neutropenia). Likewise, rhIGF-1/BP-3 treatment did not affect intestinal tissue cytokine levels (IL-1β, IL-6, IL-8, TNFα,), enterocyte proliferation, goblet cell density, permeability or bacterial translocation to the bone marrow.Conclusion: Supplemental rhIGF-1/BP-3 did not negatively affect any of the measured variables of clinical status or gut maturation in preterm pigs. Longer-term safety and efficacy of exogenous rhIGF-1/BP-3 to support maturation of the gut and other critical organs in preterm newborns remain to be investigated in both pigs and infants.

背景：重组人胰岛素样生长因子-1/结合蛋白-3（rhIGF-1/BP-3）目前正作为治疗手段应用于早产儿，但其对肠道（包括坏死性小肠结肠炎，NEC）的潜在影响尚未得到验证。本研究旨在评估rhIGF-1/BP-3在出生后最初几天内的补充是否会对生长、体力活动、血液生化及血液学等临床变量产生负面影响，以及是否会影响肠道的成熟度（例如，肠道通透性、形态学、酶活性、细胞因子水平、肠上皮细胞增殖、NEC病变），通过以NEC敏感的早产猪作为早产儿的模型进行评估。方法：早产猪每日两次接受rhIGF-1/BP-3皮下注射或对照剂。于第5天收集血液以测定IGF-1水平，并采集肠道组织用于NEC评估及生化分析。结果：与由母亲抚养的足月猪相比，早产猪的基线循环IGF-1水平较低（40 ng/mL）。rhIGF-1/BP-3治疗降低了严重NEC病变的发生率（7/24 vs. 16/24，p = 0.01）以及总体NEC的严重程度（1.8 ± 0.2 vs. 2.6 ± 0.3，p < 0.05，大部分病变发生在结肠）。在小肠中，rhIGF-1/BP-3处理组的绒毛长度（405 ± 25 vs. 345 ± 33 μm）以及刷状缘肽酶氨基肽酶N和二肽肽酶IV的活性相对于对照组猪均有所增加（+31–44%，两者均p < 0.05）。治疗对体重、血液生化或血液学没有影响，除血液白细胞和嗜中性粒细胞计数增加外（p < 0.05，即减少新生儿中性粒细胞减少症）。同样，rhIGF-1/BP-3治疗对肠道组织细胞因子水平（IL-1β、IL-6、IL-8、TNFα）、肠上皮细胞增殖、杯状细胞密度、通透性或细菌向骨髓的转移没有影响。结论：补充rhIGF-1/BP-3并未对早产猪的临床状态或肠道成熟度测量的任何变量产生负面影响。关于外源性rhIGF-1/BP-3在支持早产新生儿肠道及其他关键器官成熟方面的长期安全性和有效性，仍需在猪和婴儿身上进行进一步研究。