Table_4_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 (<20 vs. 70 ng/ml). Injection with rhIGF-1/BP-3 resulted in increased plasma IGF-1 levels for up to 6 h after injection (>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.

研究背景：重组人胰岛素样生长因子1/结合蛋白3（rhIGF-1/BP-3）目前正被测试用于早产婴儿的治疗，但该疗法对肠道的潜在影响（包括坏死性小肠结肠炎（necrotizing enterocolitis, NEC））尚未得到验证。本研究旨在以对NEC敏感的早产仔猪作为早产婴儿的动物模型，评估出生后早期补充rhIGF-1/BP-3是否会对生长、身体活动、血液生化与血液学指标、肠道成熟度（如肠通透性、肠黏膜形态、酶活性、细胞因子水平、肠上皮细胞增殖、NEC病变等）等临床变量产生负面影响。
研究方法：早产仔猪每日接受两次皮下注射rhIGF-1/BP-3或赋形剂。于第5天采集血液用于IGF-1水平检测，采集肠道组织用于NEC评估及生化分析。
研究结果：与母畜饲养的近足月仔猪相比，早产仔猪的循环IGF-1基线水平较低（<20 ng/ml vs. 70 ng/ml）。注射rhIGF-1/BP-3可使血浆IGF-1水平在注射后长达6小时内升高（>40 ng/mL）。rhIGF-1/BP-3治疗降低了重症NEC病变的发生率（7/24 vs. 16/24, p = 0.01）以及整体NEC严重程度（1.8 ± 0.2 vs. 2.6 ± 0.3, p < 0.05，且多数病变发生于结肠）。与对照组仔猪相比，rhIGF-1/BP-3治疗组仔猪的小肠绒毛长度（405 ± 25 vs. 345 ± 33 μm）以及刷状缘肽酶氨肽酶N和二肽基肽酶IV的活性均有所升高（升高幅度为31%~44%，二者p均<0.05）。该治疗对仔猪体重、血液生化或血液学指标无显著影响，仅血液白细胞及中性粒细胞计数有所升高（p < 0.05，即改善了新生儿中性粒细胞减少症）。此外，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、肠通透性或细菌易位至骨髓均无影响。
研究结论：补充rhIGF-1/BP-3并未对早产仔猪的临床状态或肠道成熟度的各项检测指标产生负面影响。外源性rhIGF-1/BP-3用于支持早产新生儿肠道及其他关键器官成熟的长期安全性与有效性，仍需在仔猪及人类婴儿中开展进一步研究。