Recombinant human insulin-like growth factor 1 complex preserves lung development in mechanically ventilated preterm lambs

RATIONALE: Bronchopulmonary dysplasia is associated with low concentrations of insulin-like growth factor 1 (IGF-1) protein in preterm infants. Postnatal replenishment of IGF-1 protein is a potential approach to prevent the decline in preterm human infants. Our recent 3-day pilot study in mechanically ventilated preterm lambs (131 days' gestation; n = 6) demonstrated downstream signaling of human IGF-1 in sheep cells in vitro and that 1.5 mg/kg/d of recombinant human (rh) IGF-1 bound to binding protein 3 (IGFBP3; rhIGF-1 complex) delivered by continuous intravenous infusion provided physiological replacement of IGF-1 protein in plasma and suggested better pulmonary outcomes. OBJECTIVE: This study assessed a longer period (7 days) of continuous treatment and larger sample size (10/group), using younger mechanically ventilated preterm lambs (128 days' gestation; equivalent to human lung development at ∼28 weeks' gestation) to allow evidence of preservation of respiratory gas exchange, alveolar formation and capillary growth, lung mechanics, and terminal bronchiole smooth muscle abundance. METHODS: Preterm lambs were mechanically ventilated for 7 days. Lambs were randomized to blinded treatment with continuous intravenous infusion of either saline (vehicle control; 5 female/5 male) or rhIGF-1 complex (5 female/5 male), starting at 6 hours after operative delivery. MEASUREMENTS AND MAIN RESULTS: RhIGF-1 complex significantly improved indices of respiratory gas exchange, alveolar formation, alveolar capillary growth, and VEGF-R2 messenger RNA expression, without adverse effects on liver or kidney function. CONCLUSIONS: RhIGF-1 complex may be an effective and safe therapy to promote functional and structural development underlying lung maturation in preterm infants and reduce the risk of developing bronchopulmonary dysplasia.