Good News for Lung Repair in Preterm Infants

In this issue of the Journal, Narayanan and colleagues (pp. 1104–1109) demonstrated with hyperpolarized helium nuclear magnetic resonance (NMR) (³HeNMR) that the alveolar number and size in preterm infants who had bronchopulmonary dysplasia (BPD) were normal at 10 to 14 years (1). This good news will change how we think about the growth and repair of the injured preterm lung. There is a developmental context for appreciating this new result. The fetal human airways branch about 17 times by about 18 weeks of gestation. A further six generations of airway branching forms the bronchioles and alveolar ducts to yield 500,000 saccules by about 32 to 34 weeks gestation (2). Amazingly, the saccular preterm human lung at 24 weeks gestation can provide gas exchange, and saccular divisions can continue until alveolarization begins. Very preterm lungs also can have altered development from antenatal exposures such as maternal smoking, fetal growth restriction, and chorioamnionitis. The preterm lung is easily injured by mechanical ventilation, oxygen, infection, and probably nutritional deficits despite the best efforts of caretakers. Although survival of these infants has increased strikingly in recent years from advances such as antenatal corticosteroids, postnatal surfactant, and more gentle approaches to mechanical ventilation, the incidence of BPD remains over 40% for infants born at 22 to 28 weeks gestation who survive to 36 weeks gestation (3).

But what is BPD? The lungs of most very low birth weight infants are not normal at term or over the first several years of life. Physiologic measurements demonstrate primarily airway abnormalities thought to represent abnormal growth (4). These infants also receive more pulmonary medications and have more lung-related hospitalizations over the first years of life than term infants (5). The BPD described by Northway and colleagues in 1967 (6) was a severe lung injury syndrome resulting from prolonged mechanical ventilation and high oxygen exposure in relatively mature infants cared for at the dawn of the use of mechanical ventilation for infants. Today, the diagnosis of BPD in very low birth weight survivors is as arbitrary point on a spectrum of lung abnormalities from mild to severe. The current understanding of the anatomy associated with BPD is based on autopsy descriptions of a delay or arrest of alveolar and pulmonary microvascular development resulting in an emphysematous-appearing lung, but without severe fibrosis (7). This understanding of the anatomy of BPD is supported by the inhibition of alveolarization into adulthood after brief oxygen exposures of the saccular newborn rodent lung. Mechanical ventilation alone can also inhibit alveolar septation in ventilated preterm sheep or baboons (8). Several older infants with severe BPD had deficits in alveolarization on biopsy (7), and Cutz and Chiasson (9) reported an alveolar deficit at 12 years of age in a child with a history of severe BPD. However, the anatomy of the lungs of the great majority of the preterm infants that survive with or without a clinical diagnosis of BPD remains unknown. I suspect that there is a highly variable range of abnormalities.

Very preterm infants must develop their lungs toward normal to survive, despite some inevitable injury. Thus, three complex processes are occurring simultaneously over months—lung development, injury, and repair. The concept has been that these infants must have catch-up alveolarization before alveolarization ceases at 2 to 3 years of age based on earlier anatomic studies reviewed by Narayanan and colleagues (1). Late deaths from progressive BPD are rare, and most children that had BPD do remarkably well as they grow. Therefore, empirically these lungs must repair, grow, and alveolarize. The time interval for that to occur has been greatly increased by the demonstration with ³HeNMR that normal alveolarization continues to at least 20 years of age (10). Although not as satisfying as seeing the anatomy, such noninvasive techniques are essential for studies of alveolarization in at-risk populations. Recently, the technique was used to demonstrate an increase in alveolar number in a 33-year-old woman following a pneumonectomy (11). Narayanan and colleagues (1) now report in the Journal that alveolar size as estimated by ³HeNMR is normal for children 10 to 14 years of age with a history of BPD. They measured alveolar size in children born at term, modestly preterm infants, infants with an average gestational age of 30 weeks with no BPD, and 28-week-gestation infants with BPD. The only abnormality was a larger standard deviation for the measurements of average alveolar dimensions for the children with a history of BPD. Although not discussed in the article, this wider standard deviation suggests to me that the infants with BPD have less uniform alveoli, perhaps a subtle abnormality. A weakness of the study is that the preterm infants were born at gestations where severe lung injury and BPD are infrequent. Further, only 9 of 18 infants had a diagnosis of moderate to severe BPD by Consensus Conference criteria (12). A population of 11-year-old children born at less than 25 weeks gestation had more abnormal pulmonary function with impaired cardiovascular performance, and decreased exercise capacity than the children reported by Narayanan and colleagues (13, 14). Populations of higher-risk survivors who had more lung injury should be evaluated for alveolarization using ³HeNMR (13, 14). I predict that abnormalities will be present.

Nevertheless, the really good news for preterm infants is that the lung has the ability to grow and alveolarize throughout childhood. Infants without severe BPD and at mean ages of 28 weeks gestation can catch up if they had an alveolarization delay during early life. Empirically, infants with birth gestations of 25 weeks or less also can grow and alveolarize their lungs, although the completeness of that development remains to be evaluated. The microanatomy of the lungs of older children who survive BPD remains essentially unknown. Caution is warranted in assuming that alveolarization and microvascular development are normal. As the human lung normally ages with a slow loss of alveoli, a theoretical concern is an accelerated loss of alveoli with aging. Hopefully, the answer is no. Technologies such as that used by Narayanan and colleagues (1) will allow us to better understand the remarkable resilience of the lungs of preterm infants across the lifespan.