Pediatric Pulmonary Biology

Pulmonary angiogenesis is essential for alveolarization, the final stage of lung development that markedly increases the gas exchange surface area of the lung. Disruption of pulmonary angiogenesis contributes to the pathogenesis of bronchopulmonary dysplasia (BPD), the most common complicationof preterm birth.  While advances in the care of preterm infants have reduced mortality, the incidence of BPD has not decreased.  Infants with BPD require significant respiratory support early in life, may have long-term deficits in pulmonary function, and are at increased risk for developing additional forms of lung disease in the future. Angiogenic factors normally increase during late lung development, but are suppressed by injuries that disrupt alveolarization; and pulmonary angiogenesis and angiogenic factors are decreased in patients dying from BPD. However, while the link between angiogenesis and alveolarization is clear, the factors that control the angiogenic program in the developing lung are not fully understood. This gap in knowledge continues to confound efforts to develop targeted therapies to treat lung diseases caused by impaired angiogenesis, including BPD. Our research aims to address this critical gap.

The Alvira lab http://alviralab.stanford.edu recently identified the transcriptional factor, nuclear factor-kappa B (NFkB), as an essential mediator of angiogenesis during alveolarization. NFkB is constitutively active in the early alveolar lung, but quiescent in the adult lung, and inhibiting NFκB disrupts pulmonary angiogenesis and alveolarization in neonatal mice, but has no effect in adults. Active NFkB in neonatal primary pulmonary endothelial cells (PEC) peaks at the onset of alveolarization, and decreases to low levels by mid-alveolarization. Blocking NFkB in neonatal PEC impairs survival, proliferation, migration and in vitro angiogenesis.  However, the capacity for NFkB to be activated is not intrinsic to the maturational state of the PEC. Conditioned media obtained from early alveolar lung organ culture (EA-LCM) robustly activates NFkB, and enhances adult PEC proliferation and migration, thus mimicking the behavior of the neonatal PEC. These data suggest that the early alveolar lung secretes unique factors that promote alveolarization by activating angiogenic pathways in the pulmonary endothelium.

Therefore, a main focus of our research program is to use proteomic analysis to compare the lung secretomes at key time points in late lung development, in order to identify novel, developmentally-regulated proteins that activate the angiogenic program in the developing lung. Given the multi-functional roles for the NFkB pathway, knowledge regarding how and when this pathway is activated in a cell-specific manner will provide essential data to facilitate the development of strategies to selectively promote (or suppress) endothelial NFkB activation in lung diseases where angiogenesis is dysregulated.  We believe that the elucidation of secreted proteins that activate the angiogenic program in the developing lung may have particular therapeutic significance, as manipulation (via replacement or blockade) would be more straightforward than targeting intracellular pathways. In addition, the identification of factors that orchestrate pulmonary angiogenesis is likely to have palpable clinical relevance even outside the neonatal period.  Adult patients with emphysema also have impaired pulmonary angiogenesis, and recent advances in stereology have shown that alveolarization continues until young adulthood.  Taken together, this information both broadens the time period when injuries may adversely impact lung structure and growth, and raises the possibility that developmental pathways could be re-invoked in order to regenerate injured alveoli outside of infancy. Thus, identification of secreted factors that promote pulmonary angiogenesis might be readily translated into novel therapeutics with potential applicability to lung diseases affecting both children and adults.

Cristina Alvira, MD Assistant Professor of Pediatrics (Critical Care)