Holgersen Kristine, Gao Xiaoyan, Narayanan Rangaraj, Gaur Tripti, Carey Galen, Barton Norman, Pan Xiaoyu, Muk Tik, Thymann Thomas, Sangild Per Torp
Comparative Pediatrics and Nutrition, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark.
Department of Neonatology, Southern Medical University Affiliated Maternal & Child Health Hospital of Foshan, Foshan, China.
Front Pediatr. 2021 Feb 4;8:602047. doi: 10.3389/fped.2020.602047. eCollection 2020.
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. 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. 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, = 0.01) and overall NEC severity (1.8 ± 0.2 vs. 2.6 ± 0.3, < 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 < 0.05). The treatment had no effects on body weight, blood chemistry or hematology, except for an increase in blood leucocyte and neutrophil counts ( < 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. 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.
重组人胰岛素样生长因子-1/结合蛋白-3（rhIGF-1/BP-3）目前正在作为一种治疗方法在早产儿中进行测试，但对肠道的可能影响，包括坏死性小肠结肠炎（NEC），尚未进行测试。本研究的目的是使用对NEC敏感的早产猪作为早产儿的模型，评估出生后最初几天补充rhIGF-1/BP-3是否会对生长、身体活动、血液化学和血液学以及肠道成熟（如肠道通透性、形态、酶活性、细胞因子水平、肠上皮细胞增殖、NEC病变）等临床变量产生负面影响。早产猪每天皮下注射两次rhIGF-1/BP-3或赋形剂。在第5天采集血液用于测量IGF-1，并采集肠道组织用于NEC评估和生化分析。与由母亲饲养的近足月猪相比，早产猪的基线循环IGF-1水平较低（<20 ng/ml对70 ng/ml）。注射rhIGF-1/BP-3导致注射后长达6小时血浆IGF-1水平升高（>40 ng/mL）。rhIGF-1/BP-3治疗降低了严重NEC病变的发生率（7/24对16/24，P = 0.01）和总体NEC严重程度（1.8±0.2对2.6±0.3，P<0.05，大多数病变发生在结肠）。在小肠中，与对照猪相比，rhIGF-1/BP-3治疗的猪的绒毛长度（405±25对345±33μm）以及刷状缘肽酶氨肽酶N和二肽基肽酶IV的活性增加（均增加31%-44%，P<0.05）。该治疗对体重、血液化学或血液学没有影响，除了血液白细胞和中性粒细胞计数增加（P<0.05，即新生儿中性粒细胞减少症减轻）。同样，rhIGF-1/BP-3治疗不影响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。补充rhIGF-1/BP-3对早产猪临床状态或肠道成熟的任何测量变量均未产生负面影响。外源性rhIGF-1/BP-3支持早产新生儿肠道和其他关键器官成熟的长期安全性和有效性仍有待在猪和婴儿中进行研究。
