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      Recent advances in our understanding of the mechanisms of lung alveolarization and bronchopulmonary dysplasia

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          Abstract

          Bronchopulmonary dysplasia (BPD) is the most common cause of morbidity and mortality in preterm infants. A key histopathological feature of BPD is stunted late lung development, where the process of alveolarization—the generation of alveolar gas exchange units—is impeded, through mechanisms that remain largely unclear. As such, there is interest in the clarification both of the pathomechanisms at play in affected lungs, and the mechanisms of de novo alveoli generation in healthy, developing lungs. A better understanding of normal and pathological alveolarization might reveal opportunities for improved medical management of affected infants. Furthermore, disturbances to the alveolar architecture are a key histopathological feature of several adult chronic lung diseases, including emphysema and fibrosis, and it is envisaged that knowledge about the mechanisms of alveologenesis might facilitate regeneration of healthy lung parenchyma in affected patients. To this end, recent efforts have interrogated clinical data, developed new—and refined existing—in vivo and in vitro models of BPD, have applied new microscopic and radiographic approaches, and have developed advanced cell-culture approaches, including organoid generation. Advances have also been made in the development of other methodologies, including single-cell analysis, metabolomics, lipidomics, and proteomics, as well as the generation and use of complex mouse genetics tools. The objective of this review is to present advances made in our understanding of the mechanisms of lung alveolarization and BPD over the period 1 January 2017–30 June 2019, a period that spans the 50th anniversary of the original clinical description of BPD in preterm infants.

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          Most cited references 624

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          A three-dimensional model of human lung development and disease from pluripotent stem cells

          Recapitulation of lung development from human pluripotent stem cells (hPSCs) in three dimensions (3D) would allow deeper insight into human development, as well as the development of innovative strategies for disease modeling, drug discovery and regenerative medicine 1 . We report here the generation from hPSCs of lung bud organoids (LBOs) that contain mesoderm and pulmonary endoderm and develop into branching airway and early alveolar structures after xenotransplantation and in Matrigel 3D culture. Expression analysis and structural features indicated that the branching structures reached the second trimester of human gestation. Infection in vitro with respiratory syncytial virus, which causes small airway obstruction and bronchiolitis in infants 2 , led to swelling, detachment and shedding of infected cells into the organoid lumens, similar to what has been observed in human lungs 3 . Introduction of mutation in HPS1, which causes an early-onset form of intractable pulmonary fibrosis 4,5 , led to accumulation of extracellular matrix and mesenchymal cells, suggesting the potential use of this model to recapitulate fibrotic lung disease in vitro. LBOs therefore recapitulate lung development and may provide a useful tool to model lung disease.
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            The new bronchopulmonary dysplasia.

             Alan Jobe (2011)
            Bronchopulmonary dysplasia (BPD) remains the most common severe complication of preterm birth. A number of recent animal models and clinical studies provide new information about pathophysiology and treatment. The epidemiology of BPD continues to demonstrate that birth weight and gestational age are most predictive of BPD. Correlations of BPD with chorioamnionitis are clouded by the complexity of the fetal exposures to inflammation. Excessive oxygen use in preterm infants can increase the risk of BPD but low saturation targets may increase death. Numerous recent trials demonstrate that many preterm infants can be initially stabilized after delivery with continuous positive airway response (CPAP) and then be selectively treated with surfactant for respiratory distress syndrome. The growth of the lungs of the infant with BPD through childhood remains poorly characterized. Recent experiences in neonatology suggest that combining less invasive care strategies that avoid excessive oxygen and ventilation, decrease postnatal infections, and optimize nutrition may decrease the incidence and severity of BPD.
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              The new BPD: an arrest of lung development.

               Alan Jobe (1999)
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                Author and article information

                Journal
                American Journal of Physiology-Lung Cellular and Molecular Physiology
                American Journal of Physiology-Lung Cellular and Molecular Physiology
                American Physiological Society
                1040-0605
                1522-1504
                December 01 2019
                December 01 2019
                : 317
                : 6
                : L832-L887
                Affiliations
                [1 ]Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
                [2 ]Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center, member of the German Center for Lung Research, Giessen, Germany
                Article
                10.1152/ajplung.00369.2019
                © 2019

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