Revisiting the Role for HIF Stabilizers in Bronchopulmonary Dysplasia

Bronchopulmonary dysplasia (BPD), a form of chronic lung disease, is a severe complication for newborns born prematurely, particularly for those born at extremely low gestational ages. The physiopathology of BPD remains incompletely understood but can be summarized by the consequence of various perinatal injuries, such as infection, mechanical ventilation, and oxygen therapy, on a predisposing field: the immature lung (1). At the histological level, BPD is primarily characterized by airspace enlargement due to defective alveolar formation, a process tightly regulated by a complex and mutually dependent relationship among pulmonary epithelial, interstitial, and endothelial cells (2). Although the past decade has allowed for improved survival of infants with extremely low gestational age, owing to antenatal glucocorticoid treatment, surfactant therapy, and less injurious neonatal resuscitation strategies, the incidence of BPD has not been reduced, and BPD, often complicated by pulmonary hypertension (PH), continues to be a major challenge for neonatologists and pediatricians. The identification of new actionable targets to prevent and treat BPD is thus a major research priority, and this is especially true as a growing body of research evidence is now available describing survivors of BPD as a population exhibiting poor neurodevelopmental outcomes together with persistent pulmonary sequelae, thus making them more susceptible to develop a variety of adult chronic lung diseases, including chronic obstructive pulmonary disease and adult PH (1, 2).

Given the multifactorial etiology of the disease, multiple preclinical animal models have been generated and continue to be optimized with the aim to better reflect the etiological complexity of BPD, understand the pathophysiological mechanisms, and test therapeutic options. Over the past 20 years, elegant studies have revealed the absolute requirement of the HIFs (hypoxia inducible 2 factors) and/or VEGF (vascular endothelial growth factor) and/or VEGF receptor signaling for microvascular lung development and associated alveolarization (3–5). In agreement with this, disruption of this signaling pathway has been documented as a common feature of animal models of BPD (1), pushing different groups to investigate whether forced activation of HIFs or their downstream targets offer therapeutic benefits. Concordant results were obtained showing that stimulation of HIF transcriptional activity secondary to inhibition of PHDs (prolyl hydroxylase domain-containing proteins) or gene therapy preserves alveolar growth in neonatal rats and preterm baboons exposed to hyperoxia (5, 6).

In this issue of the Journal, Hirsch and colleagues (pp. 1146–1158) provide additional preclinical evidence underscoring the therapeutic efficacy of HIF stabilization in attenuation and prevention of BPD (7). By combining intraamniotic injection of Escherichia coli endotoxin (mimicking human chorioamnionitis) and preterm delivery, the authors sought to determine whether prenatal stressors are sufficient to compromise alveolar development in the offspring and whether this anticipated defect could be rescue by activation of HIFs. As anticipated, reduced expression of HIF-1α and HIF-2α and their target genes (VEGF and endothelial nitric oxide synthase) decreased pulmonary vascular density, increased airspace enlargement, and increased right ventricular hypertrophy (RVH) were noticed in 14-day-old pups maternally exposed to endotoxin. Remarkably, all of these abnormalities were partially or completely cancelled on antenatal or postnatal inhibition of PHDs with dimethyloxalylglycine or GSK360A, reinforcing the notion that downregulation of HIF expression is a causal factor of impaired microvascular and alveolar growth, irrespective of the nature and timing of the insult. In direct connection with this topic, the same group also demonstrated that postnatal supplementation in IGF-1 (insulin-like growth factor 1) and its binding protein IGFBP-3, a PHD-independent positive regulator of HIF-1α expression, significantly preserves lung structure and function and prevents RVH in three different animal models of BPD, including intraamniotic injection of endotoxin (8). These findings validate promising results of a phase 2 randomized controlled trial (NCT 01096784) reporting a decrease in the occurrence of severe BPD in extremely preterm infants receiving continuous intravenous infusion of IGF-1/IGFBP-3 (9). Therefore, we could ask ourselves whether or not HIFs stabilizers will offer any additional clinical value.

Interestingly, a recent publication demonstrated that endothelial-targeted inactivation of Hif-2α induces emphysema, whereas its overexpression confers protection against emphysema (10). Together, these studies add to many others stressing that cell and molecular maintenance programs necessary for proper alveolar formation are required for maintenance of adult alveolar tissue (2). Therefore, the similarities in pathogenic mechanisms, including sustained inflammation and oxidative stress leading to epithelial and endothelial cell death, and histological features between BPD and emphysema suggest that new therapeutic advances in one of these conditions may be beneficial to the other.

Although the present study provides a better understanding of BPD pathophysiology, important questions remain to be addressed. Indeed, the authors showed that antenatal endotoxin exposure induces RVH, an indirect sign of PH, and that stabilization of HIFs abolished this clinical feature. Because abnormal activation of HIFs is a well-known trigger of vascular remodeling in adult PH, the impact of their stabilization on pulmonary vascular remodeling should be examined. To this end, histological assessment of muscularization/medial thickness of distal pulmonary arteries would be informative. Subsequently, the long-term consequences of HIF stabilization on other organs remains as something to be established.

Relevant to the important science presented in this manuscript, it is also notable that this work product was supported in part by a mentored Alpha Omega Alpha Carolyn L. Kuckein Medical Student Research Fellowship for the first author (Hirsch). Although likely a highly mentored experience and a reflection of the effort of each author in this manuscript, this is a notable achievement worth acknowledging. Developing the next generation of medical scientists is crucial and particularly challenging for potential scientists of all backgrounds. For example, with regard to physicians, a dramatic reduction in the number of physicians pursuing careers in science has occurred over the past 40 years, marked by a staggering ∼70% reduction (11). Programs that support burgeoning physicians, nonphysician scientists, and others interested in medical science are crucial to maintain and revitalize the pipeline of people prepared to lead science into the middle of this century and beyond. This manuscript is evidence of the impact funding programs such as the Kuckein Fellowship can make.

In summary, knowledge gained from the work of Hirsch and colleagues (7) provides new valuable insights into BPD pathogenesis and supports HIFs stabilizers as potential preventive agents. In so doing, the authors highlight the importance of supporting the training of our next generation of scientists.