04 February 2019

Insulin-like growth factor-1 promotes angiogenesis, prevents pulmonary hypertension and preserves lung growth in experimental models of bronchopulmonary dysplasia

Background:

Antenatal factors, such as chorioamnionitis and preeclampsia, are strongly associated with an increased risk for bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) after preterm birth. Whether IGF-1 treatment can prevent BPD is unknown.

Objective:

To evaluate whether postnatal IGF-1 treatment of newborn rats with recombinant human (rh)IGF-1/rhIGFBP-3 improves lung vascular and alveolar growth and prevents PH in 2 models of BPD induced by chorioamnionitis or preeclampsia.

Design/Methods:

Endotoxin (10 μg/sac) or sFlt-1 (1 μg/sac) was administered into the amniotic sac of pregnant rats at 20 days gestation (E20) as models of chorioamnionitis and preeclampsia, respectively. Pups were delivered by c-section at E22 and treated with rhIGF-1/rhIGFBP-3 (0.2 - 20 mg/kg/day, intraperitoneal) or buffer for 2 weeks. Study endpoints included radial alveolar counts (RAC), vessel density, and right ventricular hypertrophy (RVH) by the weight ratio (right ventricle/left ventricle+septum x 100). In addition, the effects of IGF-1 (250 ng/ml) on fetal pulmonary artery endothelial cell (PAEC) growth and tube formation was studied by standard methods in vitro.

Results:

When compared with controls, antenatal endotoxin reduced RAC and increased RVH by 42% and 72% in 2-week rats, respectively (p<0.01 for each). In the preeclampsia model, antenatal sFlt-1 reduced RAC and increased RVH by 32% and 46%, respectively (p<0.01 for each). For both models, postnatal rhIGF-1/rhIGFBP-3 treatment restored RAC to normal values and prevented RVH at all study doses when compared with placebo injections. IGF-1 stimulated growth, tube formation and upregulated VEGF and eNOS expression in fetal PAEC.

Conclusions:

Postnatal rhIGF-1/rhIGFBP-3 treatment preserved lung structure and prevented RVH in two antenatal models of BPD and enhanced angiogenic signaling in fetal PAEC. We speculate that rhIGF-1/rhIGFBP-3 treatment may provide a novel strategy for the prevention of BPD and PH, especially as associated with chorioamnionitis or preeclampsia

 

Key Contributors

Gregory Seedorf , Christina Kim, Erica Mandell, Douglas Shepherd, Steven Abman. From, the Pediatric Heart Lung Center, Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, CO 80045 USA.


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