The evolving pathophysiology of bronchopulmonary dysplasia

Abstract

Bronchopulmonary dysplasia (BPD) is the most common morbidity in very preterm infants and is characterized by abnormal development of the lung. The pathophysiology of BPD is primarily due to the effects of placental dysfunction, hyperoxia, ventilator-induced lung injury, poor nutrition, abnormal blood flow, and genomic/epigenomic factors on an immature lung. These adverse factors act on multiple cell types through many interacting signaling pathways. Abnormal development impacts most structures of the lung, including the alveoli, blood vessels, and airways, and frequently results in long-term impairment of lung mechanics and function. In this review, we provide a detailed overview of the processes involved in lung development and function and how these pathways are disrupted in BPD. The resulting effects on lung histology and lung mechanics and gas exchange are described. Insights derived from recent molecular and cellular characterization of lungs derived from normal and BPD-affected infants indicate possible mechanisms of pathogenesis and suggest potential new therapeutic strategies. The long-term implications of abnormal lung development as seen in BPD on later childhood and adult life are discussed.

Keywords: bronchopulmonary dysplasia; hyperoxia; inflammation; lung development; pulmonary hypertension.

Figure 1:. Old Bronchopulmonary Dysplasia (H&E sections; calibration bar = 25 μm):

A. Stage 1: Early stage is diffuse vascular congestion and eosinophilic hyaline membranes (arrowhead) lining distal airspaces (infant born at 30 weeks gestation, lived 1 day) B. Stage 2: Reparative injury is evident by sloughing and regenerative hyperplasia of the alveolar epithelium (arrow). Airspaces contain macrophages with organizing fibrin and have widened septa with scattered inflammatory cells (infant born at 26 weeks gestation, lived 9 days) C. Stage 3: Marked mucus secretion (*) fills proximal and distal airspaces (infant born at 24 weeks gestation, lived 13 days) D. Stage 4: In the late organized stage alveolar spaces are remodeled with interstitial fibrosis and contain increased macrophages. There is hypertrophy of bronchiolar (br) smooth muscle (infant born at 26 weeks, lung biopsy at 10 months)

Figure 2:

Timeline of BPD and pathophysiology. The pathophysiology of BPD results from abnormal lung development in the late canalicular, saccular, and alveolar stages of lung development due to preterm birth and adverse placental function exposing the developing lung to multiple adverse influences such as hyperoxia, ventilation-induced lung injury (VILI), inflammation, poor nutrition, and increased pulmonary blood flow from a patent ductus arteriosus (PDA). Genomic factors and placental function/prenatal nutritional status of the fetus also modulate lung development. This dysregulation of lung development results in inhibited alveolarization, vascular remodeling (and pulmonary hypertension in some cases), and airway remodeling, with pulmonary sequelae of extreme prematurity and BPD in adults.

Figure 3:

Histology of normal fetal lung at the (A) canalicular stage (23 weeks gestation), (B) saccular stage (31 weeks gestation) and (C) alveolar stage (40 weeks gestation) demonstrates structural alterations with age. With maturation the double capillary network (arrows) seen in the saccular stage fuses to form the thin alveolar capillary membrane evident in the alveolar stage; arrowhead designates secondary crest dividing airspaces. (H&E sections; calibration bar = 25μm).

Figure 4:

Histology of “New” BPD/chronic neonatal lung disease (CNLD). (A) Lung section from age-matched infant with normal lung development, with normal airways (arrows) and accompanying arteries, (B) Lung section from infant with BPD demonstrating markedly enlarged and simplified alveolar spaces, diminutive airways (arrows), and hypertensive changes of the pulmonary arteries (born at 26 weeks gestational age; sample from LungMAP BRINDL; D379-RLL), (C) More severe deficient alveolarization is often most conspicuous in the sub-pleural alveoli (*) (Sample from LungMAP BRINDL; D433-RLL) (H&E sections).

Figure 5:

Septal remodeling and vascular changes. (A, B) Movat pentachrome stain shows a marked increase in black elastic fiber deposition (arrows) within the alveolar ducts and septa in CNLD compared to an age-matched control (left). Also evident is medial thickening of the pulmonary veins (v). C) Medial hypertrophy of the pulmonary arteries (a) may be seen in cases with severe deficient alveolarization and clinical pulmonary hypertension. Movat pentachrome stain. D, E) Compared to an age-matched control (bottom left), CD31 immunostain highlights the reduced and abnormally dilated capillaries in the alveolar wall, which accompanies diminished secondary septation, and increased hemosiderin laden macrophages (arrowheads, iron counterstain). F) In pulmonary interstitial glycogenosis, the alveolar septa are expanded by mesenchymal cells containing vacuolated cytoplasm reflecting of glycogen. Hypertensive arterial (a) changes are often seen in diffuse pulmonary interstitial glycogenosis

Figure 6:

Airway changes. A) Tracheobronchomalacia with severe lobar hyperinflation in a tracheostomy and ventilatory dependent 15 month old male born at 25 weeks gestation. B) Histology of the distal trachea shows extensive squamous metaplasia (boxed region) of the normal ciliated columnar respiratory epithelium, including subepithelial fibrosis with loss of smooth muscle. C) Characteristic smooth muscle hyperplasia involving small airways and alveolar ducts in CNLD (LungMAP BRINDL; D379-RLL). D) Subepithelial and periairway fibrosis in the bronchiole of a 10-year-old born at 23 weeks (LungMAP BRINDL; D433-RLL).

Figure 7:

Bronchopulmonary dysplasia (BPD) by multiplexed immunofluorescence (CODEX). Panel I is hematoxylin and eosin-stained tissue microarray, serial section to panels II (includes pleura and intralobular septa) and III (same field, higher magnification, alveolar focus) that are immunostained with 40 antibodies, 6 to 7 of which are shown in each panel. A, B, C healthy pediatric lung age matched to chronic BPD in D, E, F and active evolving BPD in G, H, I. Scalebar = 500 micron. Samples from LungMAP BRINDL A-I: D096-RLL-8A1, D011-RLL-7A3, D090-RLL-7A3, D115-RLL-11A3, D227-RLL-7A2, D170-RLL-7A2, D086-RLL-11A3, D141-RLL-10A2, D169-RLL-7A2.

Figure 8:

Molecular insights into the development of bronchopulmonary dysplasia derived from single-cell transcriptomics. Derived from mouse and non-human primate models of BPD, upregulated and downregulated molecular pathways observed in alveolar macrophages, type 2 alveolar epithelial (AT2) cells, fibroblasts, and aerocyte capillary cells are shown. Red indicates upregulation in inflammation or hyperoxia-exposed lungs, while blue indicates pathways upregulated in typically developing neonatal lungs. Figure was created with a licensed version of Biorender.com

Figure 9:

Theoretical trajectory of lung mechanics (Panel A) and pulmonary vascular resistance (Panel B) in healthy subjects (green solid line), very preterm infants without BPD (dashed blue line), and extremely preterm infants with BPD (Panel A: red dot-dashed line; Panel B: red dot-dashed line for extremely preterm infants without BPD-PH and red dashed line for extremely preterm infants with BPD-PH). (Panel A is based upon initial concept by Baraldi E and Filippone M. N Engl J Med 2007 (2))