Abstract
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 3d pilot study in mechanically ventilated preterm lambs (131d 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 (7d) of continuous treatment and larger sample size (10/group), using younger mechanically ventilated preterm lambs (128d gestation; equivalent to human lung development at ∼28w 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 7d. 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 6h 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 mRNA expression, without adverse effects of liver or kidney function. CONCLUSIONS: : RhIGF-1 complex may be an effective and safe therapy to promote functional and structural development underlying the maturation of the lung in preterm infants and reducing the risk of developing bronchopulmonary dysplasia.