Assessment of inhibited alveolar‐capillary membrane structural development and function in bronchopulmonary dysplasia

Abstract

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of extreme prematurity and is defined clinically by dependence on supplemental oxygen due to impaired gas exchange. Optimal gas exchange is dependent on the development of a sufficient surface area for diffusion. In the mammalian lung, rapid acquisition of distal lung surface area is accomplished in neonatal and early adult life by means of vascularization and secondary septation of distal lung airspaces. Extreme preterm birth interrupts secondary septation and pulmonary capillary development and ultimately reduces the efficiency of the alveolar-capillary membrane. Although pulmonary health in BPD infants rapidly improves over the first few years, persistent alveolar-capillary membrane dysfunction continues into adolescence and adulthood. Preventative therapies have been largely ineffective, and therapies aimed at promoting normal development of the air-blood barrier in infants with established BPD remain largely unexplored. The purpose of this review will be: (1) to summarize the histological evidence of aberrant alveolar-capillary membrane development associated with extreme preterm birth and BPD, (2) to review the clinical evidence assessing the long-term impact of BPD on alveolar-capillary membrane function, and (3) to discuss the need to develop and incorporate direct measurements of functional gas exchange into clinically relevant animal models of inhibited alveolar development.

Initial Suppression of Transforming Growth Factor-β Signaling and Loss of TGFBI Causes Early Alveolar Structural Defects Resulting in Bronchopulmonary Dysplasia

“…7,9 Although relatively brief, lung injury incurred during the initial hospitalization affects a critical window of lung development and results in long-standing deficits in alveolar lung structure and function. 5,81,82 Attempts at preventing BPD have been largely unsuccessful, in part, because of an inadequate understanding of BPD pathogenesis. Identifying novel effectors of saccular and early alveolar development, as well as carefully understanding the developmentally appropriate context of aberrant signaling pathways after preterm birth, is critical to design therapies that promote normal alveolar lung development and function.…”

“…6,7,10 Significantly, TGF-b signaling is one of the key growth factor conduits known to influence injury, mesenchymal homeostasis, and lung development. 4,5,7,10 Although mechanically ventilated preterm infants with developing lung disease have elevated TGF-b levels in tracheal aspirates, 40,41 animal studies linking altered TGF-b signaling to arrested alveolar development are conflicted. Chronic hyperoxia impairs secondary septation and results in alveolar simplification associated with up-regulation of TGF-b.…”

Fetal lung apparent diffusion coefficient measurement using diffusion-weighted MRI at 3 Tesla: Correlation with gestational age

“…Maldevelopment of the fetal lung parenchyma may lead to life threatening physiologic dysfunction due to pulmonary hypoplasia and pulmonary hypertension (2,3). The ability to accurately assess structural lung maturation prior to delivery might be valuable as newborns with inadequate in utero lung development are at risk for respiratory failure or death after birth (4). Currently available non-invasive imaging modalities for fetal lung parenchymal assessment include volumetry by ultrasonography (US) (5) and magnetic resonance imaging (MRI) (6,7).…”

“…2,3 The ability to accurately assess structural lung maturation before delivery might be valuable as newborns with inadequate in utero lung development are at risk for respiratory failure or death after birth. 4 Currently available noninvasive imaging modalities for fetal lung parenchymal assessment include volumetry by ultrasonography (US) 5 and MRI. 6,7 Diffusion measurements can provide additional information in these studies as a potential biomarker for lung development and gestational age appropriate maturity.…”

Increased Cardiac Output and Preserved Gas Exchange Despite Decreased Alveolar Surface Area in Rats Exposed to Neonatal Hyperoxia and Adult Hypoxia

“…Despite data indicating that adult and adolescent survivors of chronic lung disease associated with extreme prematurity exhibit deficits in ventilatory control, airflow, and exercise tolerance (1)(2)(3)(4), there remains a paucity of preclinical data examining the long-term effects of neonatal lung injury on adult cardiopulmonary structure and function. Although the consequences remain unclear, consistent with the inhibition of alveolar-capillary development and increased need for oxygen supplementation observed in infants with chronic lung disease (5,6), survivors of extreme prematurity have persistent mild to moderate decreases in lung diffusing capacity (2,7,8).…”