Division of Neonatology, Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.
Division of Neonatology, Department of Pediatrics, University of California, Davis, Sacramento, CA, USA.
Pediatr Res. 2023 May;93(6):1528-1538. doi: 10.1038/s41390-022-02272-9. Epub 2022 Aug 27.
Low levels of insulin-like growth factor-1 (IGF-1) protein in preterm human infants are associated with bronchopulmonary dysplasia (BPD). We used our preterm lamb model of BPD to determine (1) dosage of recombinant human (rh) IGF-1 bound to binding protein-3 (IGFBP-3) to reach infant physiologic plasma levels; and (2) whether repletion of plasma IGF-1 improves pulmonary and cardiovascular outcomes.
Group 1: normal, unventilated lambs from 128 days gestation through postnatal age 5 months defined normal plasma levels of IGF-1. Group 2: continuous infusion of rhIGF-1/rhIGFBP-3 (0.5, 1.5, or 4.5 mg/kg/day; n = 2) for 3 days in mechanically ventilated (MV) preterm lambs determined that 1.5 mg/kg/day dosage attained physiologic plasma IGF-1 concentration of ~125 ng/mL, which was infused in four more MV preterm lambs.
Group 1: plasma IGF-1 protein increased from ~75 ng/mL at 128 days gestation to ~220 ng/L at 5 months. Group 2: pilot study of the optimal dosage (1.5 mg/kg/day rhIGF-1/rhIGFBP-3) in six MV preterm lambs significantly improved some pulmonary and cardiovascular outcomes (p < 0.1) compared to six MV preterm controls. RhIGF-1/rhIGFBP-3 was not toxic to the liver, kidneys, or lungs.
Three days of continuous iv infusion of rhIGF-1/rhIGFBP-3 at 1.5 mg/kg/day improved some pulmonary and cardiovascular outcomes without toxicity.
Preterm birth is associated with rapid decreases in serum or plasma IGF-1 protein level. This decline adversely impacts the growth and development of the lung and cardiovascular system. For this pilot study, continuous infusion of optimal dosage of rhIGF-1/rhIGFBP-3 (1.5 mg/kg/day) to maintain physiologic plasma IGF-1 level of ~125 ng/mL during mechanical ventilation for 3 days statistically improved some structural and biochemical outcomes related to the alveolar formation that would favor improved gas exchange compared to vehicle-control. We conclude that 3 days of continuous iv infusion of rhIGF-1/rhIGFBP-3 improved some physiological, morphological, and biochemical outcomes, without toxicity, in mechanically ventilated preterm lambs.
早产儿血清胰岛素样生长因子-1（IGF-1）蛋白水平较低与支气管肺发育不良（BPD）有关。我们使用早产羊 BPD 模型来确定：（1）与人胰岛素样生长因子-1（rhIGF-1）结合的重组人胰岛素样生长因子结合蛋白-3（rhIGFBP-3）的剂量，以达到婴儿生理血浆水平；（2）补充 IGF-1 是否改善肺和心血管结局。
第 1 组：从 128 天妊娠到 5 个月龄的未通气的正常绵羊定义为 IGF-1 的正常血浆水平。第 2 组：在机械通气（MV）的早产绵羊中连续输注 rhIGF-1/rhIGFBP-3（0.5、1.5 或 4.5mg/kg/天；n=2）3 天，以确定 1.5mg/kg/天的剂量可达到生理血浆 IGF-1 浓度约 125ng/mL，并在另外 4 只 MV 早产绵羊中输注。
第 1 组：血浆 IGF-1 蛋白从 128 天妊娠时的75ng/mL 增加到 5 个月时的220ng/L。第 2 组：6 只 MV 早产绵羊中最佳剂量（1.5mg/kg/天 rhIGF-1/rhIGFBP-3）的初步研究表明，与 6 只 MV 早产对照相比，某些肺和心血管结局显著改善（p<0.1）。rhIGF-1/rhIGFBP-3 对肝脏、肾脏或肺没有毒性。
3 天连续静脉输注 rhIGF-1/rhIGFBP-3 1.5mg/kg/天可改善肺和心血管结局，无毒性。
早产儿出生后血清或血浆 IGF-1 蛋白水平迅速下降。这种下降对肺和心血管系统的生长和发育产生不利影响。对于这项初步研究，在机械通气期间连续输注最佳剂量的 rhIGF-1/rhIGFBP-3（1.5mg/kg/天）以维持约 125ng/mL 的生理血浆 IGF-1 水平持续 3 天，与载体对照组相比，统计学上改善了与肺泡形成有关的一些结构和生化结局，有利于改善气体交换。我们得出结论，3 天连续静脉输注 rhIGF-1/rhIGFBP-3 可改善机械通气的早产绵羊的一些生理、形态和生化结局，无毒性。
