Bronchopulmonary dysplasia

Abstract

In the absence of effective interventions to prevent preterm births, improved survival of infants who are born at the biological limits of viability has relied on advances in perinatal care over the past 50 years. Except for extremely preterm infants with suboptimal perinatal care or major antenatal events that cause severe respiratory failure at birth, most extremely preterm infants now survive, but they often develop chronic lung dysfunction termed bronchopulmonary dysplasia (BPD; also known as chronic lung disease). Despite major efforts to minimize injurious but often life-saving postnatal interventions (such as oxygen, mechanical ventilation and corticosteroids), BPD remains the most frequent complication of extreme preterm birth. BPD is now recognized as the result of an aberrant reparative response to both antenatal injury and repetitive postnatal injury to the developing lungs. Consequently, lung development is markedly impaired, which leads to persistent airway and pulmonary vascular disease that can affect adult lung function. Greater insights into the pathobiology of BPD will provide a better understanding of disease mechanisms and lung repair and regeneration, which will enable the discovery of novel therapeutic targets. In parallel, clinical and translational studies that improve the classification of disease phenotypes and enable early identification of at-risk preterm infants should improve trial design and individualized care to enhance outcomes in preterm infants.

Conflict of interest statement

Competing interests

A.H.J. consults occasionally for Chiesi Farmaceutici about BPD and surfactant. S.H.A has served as a consultant for Takeda Pharmaceuticals. R.H.S. is a consultant for Takeda Pharmaceutical Company and for Actelion Pharmaceutical Ltd. The remaining authors declare no competing interests.

Figures

Fig. 1 |. Timeline and stages of BPD.

The timeline indicates variables that may modulate lung development from preconception through fetal development before preterm birth. Acute injury (on the timescale of days and weeks) resulting from neonatal care that is required to ensure survival then progresses to chronic lung injury and, ultimately, repair and remodelling over months and years. The unique aspect of bronchopulmonary dysplasia (BPD) is that it is an injury process that occurs as the premature lung is being injured and must repair as the lung continues to develop and mature. Remodelling of the lungs can occur over years.

Fig. 2 |. Patterns of lung disease in premature infants.

Median of the mode fraction of inspired oxygen (FiO2) on postnatal days 0 to 7 and on postnatal day 14, and the frequency of chronic lung disease (CLD) among extremely low gestational age newborns with three patterns of respiratory disease (low FiO2, pulmonary deterioration (PD) and early persistent pulmonary deterioration (EPPD)) during the first two postnatal weeks. Delineation of the three patterns of disease is useful for early prognostication of bronchopulmonary dysplasia. Some infants have minimal lung disease and recover quickly, whereas others have EPPD, which requires prolonged, substantial respiratory support from birth. In the third pattern, some infants have initial lung disease that resolves in the first week after birth and is followed by respiratory decompensation (PD) that thereafter requires mechanical ventilation and supplemental oxygen. The dashed lines are the presumed FiO2, as FiO2 was only obtained on postnatal days 7 and 14. Adapted with permission from REF., Pediatrics, 123, 1124–1131, Copyright 2009 by the AAP.

Fig. 3 |. Structure of the alveolar gas exchange region.

a | Schematic representation of the alveolar unit. Surfactant lipids (such as dipalmitoylphosphatidylcholine (DPPC)) and proteins (such as SP-B and SP-C) are produced by alveolar type 2 (AT2) cells. Surfactant is secreted onto the alveolar surface to reduce surface tension and prevent atelectasis. After secretion, surfactant lipids interact with SP-A to form tubular myelin, from which a multilayered film of surfactant lipids is produced. The surface-active phospholipids reduce surface tension at the air–liquid interface in the alveolus to prevent alveolar collapse. Surfactant lipids and proteins are recycled or degraded, the latter primarily by alveolar macrophages. Intercellular communication between alveolar epithelial cells and macrophages integrates local inflammatory signals, resulting in upregulated expression of cytokines and chemokines in response to pathogens. b | Electron microscopy image revealing the ultrastructure of the alveolus. AT2 cells contain intracellular lamellar bodies that comprise surfactant lipids and proteins. Squamous AT1 cells and endothelial cells form the gas exchange unit. Erythrocytes are seen within the alveolar capillaries of the pulmonary microvasculature. c | Confocal microscopy image of human alveoli from a 4-year-old child. On immunofluorescence imaging, anti-AGER antibody stains the surface of AT1 cells (green), anti-NKX2.1 antibody stains the nuclei of AT2 cells (white) and anti-PECAM1 antibody stains endothelial cells (red) in the microvasculature. Parts a and b adapted from REF., Springer Nature Limited.

Fig. 4 |. Human lung morphogenesis.

Schematic of the stages of lung formation from the embryonic stage to alveolarization. Changes in lung structure with advancing gestation are shown. In the embryonic period of lung bud formation, the tracheal primordium forms from the ventral region of the anterior foregut endoderm and separates from the oesophagus. During the pseudoglandular period, the lung buds proliferate and invade the splanchnic mesenchyme in the process of branching morphogenesis to form the airways and peripheral acinar buds, the latter forming the alveoli later in development. During the saccular stage, epithelial cells lining conducting airways differentiate, producing basal, goblet, ciliated and other secretory cells, which are distinct from the epithelial cells lining the peripheral saccules, namely the cuboidal pre-alveolar type 2 (AT2) cells and squamous AT1 cells. In the saccular–alveolar transition, the peripheral saccules further dilate and the surface is increasingly covered by AT1 cells as the gas exchange region expands. AT2 cells differentiate and produce increasing amounts of surfactant lipid and proteins, which are stored in lamellar bodies. Lung growth continues until adolescence. Adapted with permission from REF., Oxford University Press.

Fig. 5 |. Structural changes in the lung during development and in BPD.

a–d | Developmental changes in lung structure revealed by immunofluorescence and confocal microscopy of a mouse lung at the pseudoglandular (embryonic day 16.5 (E16.5); part a), canalicular (E18.5; part b), saccular (postnatal day 3 (P3); part c) and alveolar (P28; part d) stages of lung development. The transcription factor NKX2.1 (light blue) is required for lung morphogenesis and is expressed by the epithelial cells lining the trachea, bronchi and peripheral lung tubules. An anti-EMCN antibody stains endothelial cells (red) in the developing microvasculature. An anti-ACTA2 antibody stains smooth muscle cells (white) in pulmonary vessels in the bronchial, submucosal and alveolar regions. Smooth muscle actin (ACTA2) staining is prominent on P3 during active alveolar formation (part c) and is less prominent on P28 (part d). e–f | Simplification of alveolar structure in bronchopulmonary dysplasia (BPD). Confocal microscopy images of a section of the lung of a healthy infant (part e) and that of an infant with BPD (part f) at ~3 years of age. Alveolar surfaces are primarily lined by squamous alveolar type 1 (AT1) cells, which are stained with anti-AGER antibodies (green). An anti-PECAM1 antibody stains endothelial cells (red) in pulmonary capillaries. An anti-NKX2.1 antibody selectively stains AT2 cells (white). Alveoli form by septation, creating numerous small saccules in the normal lung (part e), whereas the alveoli are enlarged or ‘simplified’ in the lungs of an infant with BPD (part f), causing loss of the alveolar–capillary gas exchange surface area.

Fig. 6 |. Pulmonary vascular disease in BPD.

a | Prevalence of pulmonary hypertension in preterm infants, as assessed by echocardiography at 36 weeks post-menstrual age. Pulmonary hypertension was diagnosed in 14–25% of preterm infants in different cohorts (Seoul, Korea; Alabama, USA; and Colorado (CO) and Indiana (CU/IU), USA), with the highest incidence of pulmonary hypertension associated with severe bronchopulmonary dysplasia (BPD). b–d | Early pulmonary vascular disease, as assessed by echocardiography on postnatal day 7, is strongly associated with adverse outcomes, including severe BPD (part b), risk of pulmonary hypertension (PH) at 36 weeks (part c) and risk of respiratory disease during the first 2 years of life,, (part d). ER, emergency room. Part a adapted with permission from REF., Elsevier. Parts b and c adapted with permission from REF., of the American Thoracic Society. Copyright 2019 American Thoracic Society. Part d adapted with permission from REF., of the American Thoracic Society. Copyright 2019 American Thoracic Society.

Fig. 7 |. Alternative ventilation strategies in the treatment of heterogeneous lung disease in severe BPD.

Schematic of the physiological effects of small-volume, rapid-rate ventilator support (panel a) and larger tidal volume, prolonged inspiratory time strategies (panel b) in a lung that contains regional heterogeneity in the severity of lung disease, as is observed in infants with severe bronchopulmonary dysplasia (BPD). a | Small tidal volume breaths probably increase dead space ventilation, leading to atelectasis, hypercapnia and high oxygen requirements. b | Increased tidal volumes and inspiratory times may enhance the distribution of gas, leading to lower oxygen requirements, improved ventilation and less atelectasis. Compliance (C) is a measure of the lung’s ability to stretch and expand (distensibility of elastic tissue). Resistance (R) is the resistance of the respiratory tract to airflow during inhalation and expiration. FiO2, fraction of inspired oxygen; PCO2, partial pressure of carbon dioxide; VD, dead-space ventilation; VT, tidal ventilation. Adapted with permission from REF., Elsevier.

Fig. 8 |. Structural changes in the lungs in severe BPD.

a | Serial high-resolution CT scans illustrate time-related changes in lung architecture with regional heterogeneity in an infant with severe bronchopulmonary dysplasia (BPD). Extensive remodelling occurs over time, but persistent lung hyperinflation with abnormal lung parenchyma persists at 23 months. b | Chest CT scan of an 8-year-old girl who was born at 26 weeks gestation and had a history of severe bronchopulmonary dysplasia and pulmonary hypertension. Part a reproduced with permission from REF., Elsevier.

Fig. 9 |. Persistent subclinical pulmonary vascular disease in BPD.

a | After extreme preterm birth (average gestational age of 27 weeks), several echocardiography-based studies demonstrate lower pulmonary artery acceleration time (PAAT) beyond infancy into early adolescence, suggesting higher pulmonary vascular pressure and resistance,–. b | Mean pulmonary artery pressure (mPAP) is consistently highest during adolescence and early adulthood among those who were preterm infants with bronchopulmonary dysplasia (BPD),. *P < 0.05 by two-way ANOVA with Sidak’s multiple comparisons test.