Chronic lung disease in the preterm infant. Lessons learned from animal models

Abstract

Neonatal chronic lung disease, also known as bronchopulmonary dysplasia (BPD), is the most common complication of premature birth, affecting up to 30% of very low birth weight infants. Improved medical care has allowed for the survival of the most premature infants and has significantly changed the pathology of BPD from a disease marked by severe lung injury to the "new" form characterized by alveolar hypoplasia and impaired vascular development. However, increased patient survival has led to a paucity of pathologic specimens available from infants with BPD. This, combined with the lack of a system to model alveolarization in vitro, has resulted in a great need for animal models that mimic key features of the disease. To this end, a number of animal models have been created by exposing the immature lung to injuries induced by hyperoxia, mechanical stretch, and inflammation and most recently by the genetic modification of mice. These animal studies have 1) allowed insight into the mechanisms that determine alveolar growth, 2) delineated factors central to the pathogenesis of neonatal chronic lung disease, and 3) informed the development of new therapies. In this review, we summarize the key findings and limitations of the most common animal models of BPD and discuss how knowledge obtained from these studies has informed clinical care. Future studies should aim to provide a more complete understanding of the pathways that preserve and repair alveolar growth during injury, which might be translated into novel strategies to treat lung diseases in infants and adults.

Figure 1.

Pathophysiologic changes to the developing lung after exposure to oxygen and shear stress. Normal lung development is depicted on the Ieft; abnormal processes are depicted on the right. ECM, extracellular matrix; HIF, hypoxia-inducible factor; MMP, matrix metalloproteinase; VEGF-A, vascular endothelial growth factor A; VEGF-R1, vascular endothelial growth factor receptor 1; VEGF-R2, vascular endothelial growth factor receptor 2.