Browsing by Subject "Neonatal lung morphogenesis"

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    Assessment of inhibited alveolar-capillary membrane structural development and function in bronchopulmonary dysplasia
    (Wiley, 2014-03) Ahlfeld, Shawn K.; Conway, Simon J.; Department of Medicine, IU School of Medicine
    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.
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    Periostin Downregulation Is an Early Marker of Inhibited Neonatal Murine Lung Alveolar Septation
    (Wiley, 2013) Ahlfeld, Shawn K.; Gao, Yong; Wang, Jian; Horgusluoglu, Emrin; Bolanis, Esther; Clapp, D. Wade; Conway, Simon J.; Pediatrics, School of Medicine
    Background: Extreme preterm birth exposes the saccular lung to multiple teratogens, which ultimately retard alveolar development. Specifically, therapeutic high level oxygen supplementation adversely affects the premature lungs and results in blunted alveolarization. Prolonged hyperoxic lung injury has previously been shown to upregulate the matricellular protein Periostin (Postn) and stimulate ectopic accumulation of alpha smooth muscle actin (αSMA) myofibroblasts. Therapies that promote lung septation are lacking largely due to a lack of reliable early biomarkers of injury. Thus, we determined if Postn expression correlated with the initial appearance of myofibroblasts in the saccular lung and was required for early alveolar development. Methods: Lung development in C57BL/6J mice following room-air (RA, 21%-O₂) or continuous hyperoxia (85%-O₂) from birth (P0) through postnatal day P14 was correlated with Postn and αSMA expression. Alveolarization in Postn knockout mice exposed to room-air, 60%-, and 85%-O₂ was also examined. Results: Postn was widely expressed in distal lung septa through P2 to P4 and peak expression coincided with accumulation of saccular myofibroblasts. Initially, 85%-O₂ prematurely downregulated Postn and αSMA expression and suppressed proliferation before the first evidence of distal lung simplification at P4. By P14, chronic 85%-O₂ resulted in secondary upregulation of Postn and αSMA in blunted septa. Myofibroblast differentiation and alveolar development was unaffected in Postn null mice and acute 85%-O₂ exposure equally inhibited septal formation in Postn null and wild-type littermates. Conclusion: Postn expression is tightly correlated with the presence of αSMA-myofibroblasts and is a novel early biomarker of acutely inhibited alveolar septation during a crucial window of lung development.