Growth of Pulmonary Microvasculature in Ventilated Preterm Infants

Abstract

Rationale: Density-based morphometric studies have demonstrated decreased capillary density in infants with bronchopulmonary dysplasia (BPD) and in BPD-like animal models, leading to the prevailing view that microvascular development is disrupted in BPD. Objective: To perform a comprehensive analysis of the early and late effects of ventilation on pulmonary microvascular growth in preterm infants. Methods: Postmortem lung samples were collected from ventilated preterm infants who died between 23 and 29 wk ("short-term ventilated") or between 36 and 39 wk ("long-term ventilated") corrected postmenstrual age. Results were compared with age-matched infants or stillborn infants ("early" and "late" control subjects). Microvascular growth was studied by anti-platelet endothelial cell adhesion molecule (PECAM)-1 immunohistochemistry, quantitative stereology, analysis of endothelial cell proliferation, and Western blot analysis of pulmonary PECAM-1 protein levels. Measurements: Measurements were made of capillary density, volume of air-exchanging parenchyma, volume of microvascular endothelial cells, Ki67 labeling index of endothelial cells, and PECAM-1/actin protein levels. Main Results: Lungs of long-term ventilated infants showed a significant (more than twofold) increase in volume of air-exchanging parenchyma and a 60% increase in total pulmonary microvascular endothelial volume compared with late control subjects, associated with 60% higher pulmonary PECAM-1 protein levels. The marked expansion of the pulmonary microvasculature in ventilated lungs was, at least partly, attributable to brisk endothelial cell proliferation. The microvasculature of ventilated lungs appeared immature, retaining a saccular architectural pattern. Conclusions:The pulmonary microvasculature of ventilated preterm infants displayed marked angiogenesis, nearly proportionate to the growth of the air-exchanging lung parenchyma. These results challenge the paradigm of microvascular growth arrest as a major pathogenic factor in BPD.Keywords: bronchopulmonary dysplasia; chronic lung disease of prematurity; neonatal lung disease Despite major advances in perinatal medicine, including the introduction of surfactant therapy, antenatal glucocorticoids, and new ventilator strategies, preterm newborns treated with ventilation and supplemental oxygen frequently develop bronchopulmonary dysplasia (BPD), a chronic lung disease of newborn infants associated with significant mortality and morbidity (1). BPD in the postsurfactant era is seen primarily in very low birth weight infants and affects 30% of infants born at 24 to 28 wk, many of whom will require long-term ventilation and/or supplemental oxygen (2, 3).The dominant pathologic finding at autopsy in postsurfactant BPD is an arrest in alveolar development, resulting in lungs with large and simplified airspaces showing varying degrees of interstitial fibrosis (2, 4-8). Impairment of alveolar formation in BPD leads to long-term global reduction in alveolar number and gas-exchange surface area (6, 7). The ...

Bombesin-like Peptides Modulate Alveolarization and Angiogenesis in Bronchopulmonary Dysplasia

“…In contrast, De Paepe and colleagues have described an increase in total pulmonary microvascular endothelial cell volume in long-term ventilated infants (8). However, the observations of ''short-term ventilated preterm infants'' by De Paepe and colleagues are completely consistent with the results of our current investigation.…”

“…However, BPD is still a major burden in pediatric medicine, paradoxically due to success in improving acute survival. BPD affects approximately 30% of infants weighing less than 1,000 g. ''Modernday BPD,'' occurring in infants less than 30 weeks' gestation, seems to have a different pathophysiology and is characterized by arrested alveolar development and microvascular defects (3,(5)(6)(7)(8).Although many animal models of BPD have been described (9-15), BPD in preterm baboons is most similar to human BPD clinically and pathologically. The original hyperoxic BPD model was in animals at 140 days' gestation (term 5 180 d) given 100% O 2 for 10 days (140-day 100%) (16, 17), which develop acute respiratory distress syndrome followed by severe BPD similar to old BPD (18).…”

“…However, BPD is still a major burden in pediatric medicine, paradoxically due to success in improving acute survival. BPD affects approximately 30% of infants weighing less than 1,000 g. ''Modernday BPD,'' occurring in infants less than 30 weeks' gestation, seems to have a different pathophysiology and is characterized by arrested alveolar development and microvascular defects (3,(5)(6)(7)(8).…”

Bronchopulmonary dysplasia and emphysema: in search of common therapeutic targets

“…The previously proposed paradigm that microvascular growth arrest due to decreased angiogenic mediators [49] is a major pathogenic factor may not be completely accurate, however, since marked angiogenesis has been reported in long-term ventilated infants [50].…”

Fas-Ligand-Induced Apoptosis of Respiratory Epithelial Cells Causes Disruption of Postcanalicular Alveolar Development

“…3,4 In addition, the lungs of infants with BPD show structurally abnormal microvasculature and variable degrees of interstitial fibrosis. 5,6 The BPD currently observed in extremely premature infants has been termed "new" BPD to differentiate this condition from the pathologically and epidemiologically distinct historical BPD, originally described in the late 1960s by Northway and colleagues. 7 The latter occurred in less premature infants and was characterized by more severe patterns of acute lung and airway injury.…”