B. Wallace1,2, G. Seedorf1, A. Peisl1, S. H. Abman1 1University Of Colorado Denver,Pediatric Heart Lung Center, Department Of Pediatrics,Aurora, CO, USA 2University Of Colorado Denver,Department Of General Surgery,Aurora, CO, USA
Introduction:
Epidemiologic studies have shown the risk for bronchopulmonary dysplasia (BPD) is increased in pregnancies complicated by preeclampsia (PE). However, mechanisms linking PE with the pathogenesis of BPD and therapies for prevention remain unknown. Past clinical studies of PE have consistently reported high levels of soluble fms-like tyrosine kinase 1 (sFlt-1), an endogenous antagonist to vascular endothelial growth factor, in maternal blood and amniotic fluid. Furthermore, cord blood levels of sFlt-1 are increased in preterm neonates who subsequently develop BPD. We have previously shown intra-amniotic (IA) sFlt-1 exposure in infant rats causes sustained abnormalities of lung growth and pulmonary hypertension (PH) that mimic clinical BPD. Therefore, we hypothesize that administration of an anti-sFlt-1 monoclonal antibody (Mab) would prevent the abnormal lung structure and PH in experimental BPD caused by IA sFlt-1 exposure. We further hypothesize that antenatal Mab treatment may be a more effective strategy than postnatal therapy.
Methods:
We studied the effects of anti-sFlt-1 Mab treatment in infant Sprague-Dawley rats after IA sFlt-1 (1 μg/sac) at 20 days gestation (E20; term 22 days). We compared 3 different Mab treatment strategies: 1) IA injection (1.5 μg/sac) at E20 alone; 2) postnatal injections (1 mg/kg) on alternate days up to 2 weeks; and 3) antenatal maternal uterine artery injection (1 mg/kg) at E20 alone. Pups were delivered on E22 by c-section and observed for 14 days after delivery. Pups were then killed and the lungs inflated and fixed with 4% paraformaldehyde for histology. Alveolarization was assessed by radial alveolar counts (RAC) and evidence of PH measured by right ventricular hypertrophy (RVH) as reflected by the weight ratio of right ventricle to left ventricle plus septum.
Results:
Antenatal sFlt-1 reduced RAC by 37% and increased RVH by 64% versus controls (p<0.0001, respectively). Anti-sFlt-1 Mab treatment preserved lung growth as assessed by RAC when compared to sFlt-1 alone for all treatment strategies (Figure 1). Antenatal IA anti-sFlt-1 Mab treatment decreased RVH by 20% compared to sFlt-1 exposed pups (p<0.003), whereas postnatal and maternal anti-sFlt-1 Mab treatment of sFlt-1 exposed pups completely prevented RVH (Figure 1).
Conclusion:
We conclude that anti-sFlt-1 Mab preserves lung growth in infant rats after IA exposure to sFlt-1. Furthermore, whereas antenatal IA treatment effectively protected lung structure, only postnatal and maternal treatment strategies additionally completely prevented PH throughout infancy. We speculate that anti-sFlt-1 Mab therapy may provide a novel strategy for the prevention of BPD in preterm infants who were born from pregnancies complicated by PE.
