Bronchopulmonary dysplasia (BPD), the chronic lung disease that follows premature birth, remains a major cause of morbidity and mortality. BPD is characterized by an arrest of vascular and alveolar growth and high risk for pulmonary hypertension (PH), yet mechanisms contributing to its pathogenesis and early strategies to prevent BPD are poorly understood. Strong epidemiologic studies have shown that the ?new BPD? largely reflects the long-lasting impact of antenatal factors on lung development partly due to vascular dysfunction, yet data from animal models exploring underlying mechanisms of how prenatal injury contributes to BPD are limited. Our recent prospective clinical studies have shown that antenatal determinants as assessed on the first day of life and early echocardiogram findings of PH are strongly linked with the subsequent diagnosis of BPD at 36 weeks PMA. As highlighted in recent NIH workshops, studies that define mechanisms through which antenatal stress increases the risk for BPD and PH and early strategies that accurately identify at-risk preterm infants are high research priorities. Vascular endothelial growth factor (VEGF), a potent endothelial cell mitogen and angiogenic factor, plays an essential role during normal lung development. We have previously shown that disruption of VEGF signaling impairs lung vascular growth, decreases alveolarization and causes PH in experimental BPD, and that the effects of VEGF are largely mediated through increased endothelial production of ?angiocrine factors,? which mediate endothelial-epithelial interactions and are necessary for normal distal lung growth. Based on work from our prior funding period, we hypothesize that antenatal stress disrupts angiogenic signaling and impairs the production of critical angiocrine factors in the fetal lung that lead to sustained abnormalities of lung structure and PH after birth. More specifically, we seek to determine whether antenatal disruption hypoxia-inducible factor (HIF) - VEGF - insulin-like growth factor 1 (IGF-1) signaling in the fetal lung contributes to the pathobiology of BPD. We propose a series of translational studies that link in vivo models of preeclampsia and chorioamnionitis with in vitro studies using lung explants, isolated cell systems and molecular approaches to determine whether augmentation of HIF-VEGF-IGF-1 signaling and related downstream signaling pathways can be targeted for developing new preventive therapies. We will further apply novel imaging strategies to precisely define the impact of antenatal stress on distal lung architecture and cell-cell interactions at the microvascular and epithelial interface, and will perform parallel studies with clinical lung tissue from fatal human BPD. Finally, to translate these findings to human disease, we propose to identify early changes in proteomic markers of angiogenic pathways to link antenatal stress with high risk for BPD from our clinical database. Overall, these studies will yield new information regarding potential mechanisms through which adverse prenatal events alter fetal lung vascular growth and function, leading to persistent abnormalities of lung structure and function. By integrating preclinical and clinical studies, we hope to provide insights into disease mechanisms and discover biomarkers related to angiocrine signaling that will enable the early identification of preterm infants at risk for BPD and ultimately lead to the development of successful preventative strategies.
Epidemiologic studies strongly link complications of pregnancy with high risk for bronchopulmonary dysplasia (BPD) after premature birth, but mechanisms through which prenatal stress causes persistent respiratory disease are uncertain. This project will determine whether antenatal disruption of angiogenesis and angiocrine signaling as related to impaired VEGF signaling causes persistent abnormalities of lung vascular and alveolar structure in relevant animal models. Proteomic studies and lung tissue analysis of human BPD will further pursue this hypothesis in the clinical setting.
| Singh, Jasmine N; Nowlin, Taylor M; Seedorf, Gregory J et al. (2017) Quantifying three-dimensional rodent retina vascular development using optical tissue clearing and light-sheet microscopy. J Biomed Opt 22:76011 |
