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. 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. : 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. 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. : 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.

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.

Novel therapies are needed for bronchopulmonary dysplasia (BPD) because no effective treatment exists. Mesenchymal stromal cell extracellular vesicles (MSC-sEVs) have therapeutic efficacy in a mouse pup neonatal hyperoxia BPD model. We tested the hypothesis that MSC-sEVs will improve lung functional and structural development in mechanically ventilated preterm lambs. Preterm lambs (∼129 days; equivalent to human lung development at ∼28 wk gestation) were exposed to antenatal steroids, surfactant, caffeine, and supported by mechanical ventilation for 6-7 days. Lambs were randomized to blinded treatment with either MSC-sEVs (human bone marrow MSC-derived; 2 × 1011 particles iv; n = 8; 4 F/4 M) or vehicle control (saline iv; 4 F/4 M) at 6 and 78 h post delivery. Physiological targets were pulse oximetry O2 saturation 90-94% ([Formula: see text] 60-90 mmHg), [Formula: see text] 45-60 mmHg (pH 7.25-7.35), and tidal volume 5-7 mL/kg. MSC-sEVs-treated preterm lambs tolerated enteral feedings compared with vehicle control preterm lambs. Differences in weight patterns were statistically significant. Respiratory severity score, oxygenation index, A-a gradient, distal airspace wall thickness, and smooth muscle thickness around terminal bronchioles and pulmonary arterioles were significantly lower for the MSC-sEVs group. S/F ratio, radial alveolar count, secondary septal volume density, alveolar capillary surface density, and protein abundance of VEGF-R2 were significantly higher for the MSC-sEVs group. MSC-sEVs improved respiratory system physiology and alveolar formation in mechanically ventilated preterm lambs. MSC-sEVs may be an effective and safe therapy for appropriate functional and structural development of the lung in preterm infants who require mechanical ventilation and are at risk of developing BPD.NEW & NOTEWORTHY This study focused on potential treatment of preterm infants at risk of developing bronchopulmonary dysplasia (BPD), for which no effective treatment exists. We tested treatment of mechanically ventilated preterm lambs with human mesenchymal stromal cell extracellular vesicles (MSC-sEVs). The results show improved respiratory gas exchange and parenchymal growth of capillaries and epithelium that are necessary for alveolar formation. Our study provides new mechanistic insight into potential efficacy of MSC-sEVs for preterm infants at risk of developing BPD.

Background 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. Methods 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. Results 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. Conclusions 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. Impact 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.

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The diagnosis of congenital diaphragmatic hernia (CDH) is associated with significant morbidity and mortality. Survival of neonates with CDH has improved recently, although the clinical course is complicated by sequelae of hypoplastic pulmonary parenchyma and vasculature, pulmonary hypertension, ventilation/perfusion (V/Q) mismatch, reduced pulmonary function and poor somatic growth. In this case report, we describe an infant with an antenatal diagnosis of CDH with a poor prognosis who underwent initial surgery followed by a tracheostomy but had a worsening clinical course due to a large area of ventilated but poorly perfused lung based on a V/Q nuclear scintigraphy scan. The emphysematous left lung was causing mediastinal shift and compression of the right lung, further compromising gas exchange. The infant had clinical improvement following bronchial blockade of the under-perfused left lung. This paved the way for further management with resection of the under-perfused lung lobe and continued clinical improvement. We present the novel use of selective bronchial blockade in a challenging case of CDH to determine if surgical lung resection may benefit the infant. We also review the physiology of gas exchange during the use of a bronchial occluder and the relevant literature.

Invasive mechanical ventilation (IMV) and exposure to oxygen-rich gas during early postnatal life are contributing factors for long-term pulmonary morbidities faced by survivors of preterm birth and bronchopulmonary dysplasia. The duration of IMV that leads to long-term pulmonary morbidities is unknown. We compared two durations of IMV (3 h vs. 6 days) during the first 6–7 days of postnatal life in preterm lambs to test the hypothesis that minimizing the duration of IMV will improve long-term respiratory system mechanics and structural outcomes later in life. Moderately preterm (∼85% gestation) lambs were supported by IMV for either 3 h or 6 days before weaning from all respiratory support to become former preterm lambs. Respiratory system mechanics and airway reactivity were assessed monthly from 1 to 6 mo of chronological postnatal age by the forced oscillation technique. Quantitative morphological measurements were made for smooth muscle accumulation around terminal bronchioles and indices of alveolar formation. Minimizing IMV to 3 h led to significantly better ( P < 0.05) baseline respiratory system mechanics and less reactivity to methacholine in the first 3 mo of chronological age (2 mo corrected age), significantly less ( P < 0.05) accumulation of smooth muscle around peripheral resistance airways (terminal bronchioles), and significantly better ( P < 0.05) alveolarization at the end of 5 mo corrected age compared with continuous IMV for 6 days. We conclude that limiting the duration of IMV following preterm birth of fetal lambs leads to better respiratory system mechanics and structural outcomes later in life.

Pulmonary angiogenesis is a key driver of alveolarization. Our prior studies showed that NF-kappa B promotes pulmonary angiogenesis during early alveolarization. However, the mechanisms regulating temporal-specific NF-kappa B activation in the pulmonary vasculature are unknown. To identify mechanisms that activate proangiogenic NF-kappa B signaling in the developing pulmonary vasculature, proteomic analysis of the lung secretomewas performed using two-dimensional difference gel electrophoresis. NF-kappa B activation and angiogenic function was assessed in primary pulmonary endothelial cells (PECs) and TGFBI (transforming growth factor-beta-induced protein)-regulated genes identified using RNA sequencing. Alveolarization and pulmonary angiogenesis was assessed in wild-type and Tgfbi null mice exposed to normoxia or hyperoxia. Lung TGFBI expression was determined in premature lambs supported by invasive and noninvasive respiratory support. Secreted factors from the early alveolar, but not the late alveolar or adult lung, promoted proliferation and migration in quiescent, adult PECs. Proteomic analysis identified TGFBI as one protein highly expressed by the early alveolar lung that promoted PEC migration by activating NF-kB via avb3 integrins. RNA sequencing identified Csf3 as a TGFBI-regulated gene that enhances nitric oxide production in PECs. Loss of TGFBI in mice exaggerated the impaired pulmonary angiogenesis induced by chronic hyperoxia, and TGFBI expression was disrupted in premature lambs with impaired alveolarization. Our studies identify TGFBI as a developmentally regulated protein that promotes NF-kappa B-mediated angiogenesis during early alveolarization by enhancing nitric oxide production. We speculate that dysregulation of TGFBI expression may contribute to diseases marked by impaired alveolar and vascular growth.

Purpose of study Prolonged mechanical ventilation (MV) of premature infants leads to lung injury. Frequently, the brain is injured. Our studies, using preterm lambs, indicate that MV from 3 d to 21 d shifts balance to more apoptosis and less proliferation of neurons, immature and mature oligodendrocytes, and astrocytes. These results are consistent with less brain-derived neurotrophic factor in the same brain tissue. Methods used We hypothesised that progressively longer period of MV will alter presence of neural stem cells and neuronal progenitor cells, as well as capillaries in the brain. Preterm lambs, treated with antenatal steroids and postnatal surfactant, were managed by MV or high-frequency nasal ventilation (HFNV) for either 3 d or 21 d (n=4/group). We use HFNV as the positive gold-standard for alveolar formation in the lung. At the end of 3 d or 21 d, cortical brain tissue from the temporal lobe was fixed. We used immunohistochemistry to localise Nestin-positive neural stem cells, double cortin (DCX)-positive neuronal progenitor cells, and p-glycoprotein-positive capillaries. We used stereology to quantify surface density of each cell type in cortical grey matter, using systematic, uniform, random sampling. Summary of results Initial results for n=2/group are summarised. Surface density (Sv; cm-1) for Nestin-positive cells appears to increase from 3 d to 21 d of MV (average Sv 5 and 46, respectively), and from 3 d to 21 d HFNV (average Sv 7 and 19, respectively). Sv for DCX-positive cells appears to decrease from 3 d to 21 d of MV (average Sv 94 to 71, respectively), and from 3 d to 21 d HFNV (average Sv 95 and 54, respectively). Sv for capillaries also appears to decrease from 3 d to 21 d of MV (average Sv 84 to 67, respectively), and from 3 d to 21 d HFNV (average Sv 101 and 71, respectively). Conclusions Contrary to our hypothesis, these initial results suggest that preterm birth and any ventilatory support may change the proportion of neural stem cells (Nestin-positive cells), neuronal progenitor cells (DCX-positive cells), and capillaries (p-glycoprotein-positive microvessels) in the brain as the duration of respiratory support increases. Analyses are ongoing to increase sample size. HL110002.