Northway et al. (1) described bronchopulmonary dysplasia (BPD) in 1967, in a group of large preterm infants, as severe lung injury resulting from mechanical ventilation and oxygen exposure. Subsequently, many aspects of the injury were reproduced by oxygen exposure of newborn mice (2). O'Brodovich and Mellins (3) reviewed BPD in 1985, emphasizing that the combination of oxidant injury and mechanical ventilation resulted in inflammation, fibrosis, and smooth muscle hypertrophy in the airways. With progress in neonatal care that includes antenatal glucocorticoids, surfactant treatments, and gentler ventilation strategies, large preterm infants seldom develop BPD. However, the disease today is the most common complication of care of infants born weighing <1 kg (4). Further, BPD occurs frequently in infants weighing <1 kg who do not have much lung disease soon after birth (5, 6). Therefore, the traditional tandem of oxygen and barotrauma is not the major factor initiating much of the lung injury in very preterm infants. If the infants are more immature and the causes of injury are not primarily mechanical ventilation and oxidant injury, the pathology likely will be different. Although multiple pathophysiologic mechanisms no doubt contribute to lung injury in the preterm, the new BPD may be primarily an aberration of lung development (Fig. 1).

Figure 1
figure 1

The new BPD in very low birth weight infants.

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Infants born at 24–28 wk gestation are just beginning to alveolarize the distal saccules of the lung in parallel with development of the alveolar capillary bed. Hislop et al. (7) reported that ventilation of low birth weight infants yielded lungs with fewer alveoli. Husain et al. (8) recently reported that infants dying of BPD in the recent era of surfactant treatment had fewer and larger alveoli with less striking fibrosis and inflammation than in the past. Stahlman has found remarkable histopathology in infants dying of BPD after several months of ventilation. The lungs have minimal inflammation or fibrosis, but the saccular lung seems to have an arrest in alveolar and vascular development corresponding to the gestation of the infant at delivery (M.T. Stahlman, personal communication). These observations suggest, at least in infants dying of BPD, that the major manifestation of lung injury is an interference with normal lung development.

This arrest of lung development can be reproduced in preterm animals. Coalson et al. (9) found that exposure of baboons delivered at 140 d gestation (term is 186 d) to 100% oxygen and ventilation for 7 d decreased alveolar number by approximately 50% when the animals were 33 wk old relative to preterm baboons ventilated with less oxygen. This study emphasized the old association of oxygen with BPD. However, a similar pathology also occurred if baboons were delivered at 125 d gestation, surfactant-treated, and ventilated with <50% oxygen. Albertine et al. (10) ventilated 125-d-gestation surfactant-treated preterm lambs (term is 150 d) for 3 wk by using routine ventilation strategies and minimal supplemental oxygen. They found a complete arrest of alveolar septation that resulted in fewer and larger alveoli. Vascular development also was arrested. The animal models and clinical correlates show that the new BPD is characterized by an arrest of lung development and that the traditional indicators of injury are less evident.

WHAT REGULATES ALVEOLARIZATION?

The normal signals for alveolar septation are not known. However, in experimental animals, alveolar development can be delayed with hypoxia or hyperoxia, glucocorticoids, or poor nutrition (11). Transgenic mice provide some clues about factors that can disrupt lung development. Overexpression of TNF-α in the pulmonary epithelium during development results in decreased alveolar number and inflammation (12). Overexpression of TGF-α results in fewer and larger alveoli and fibrosis (13). Overexpression of IL-11 in the airways of newborn mice also results in fewer and larger alveoli, and overexpression of IL-6 causes lymphocytic infiltrate in the lungs and fewer and larger alveoli (14, 15). The common thread is that cytokine overexpression can interfere with the normal postnatal alveolarization in mice. The glucocorticoid-induced inhibition of alveolarization can be blocked in newborn rats with retinoic acid (16). These observations tell us what can interfere with alveolarization but do not provide insights into the normal signals for alveolar development.

LUNG MATURATION

The human fetal lung normally is not mature clinically until after approximately 35 wk gestation. In contrast, 26-wk-gestation infants with essentially no lung disease are frequent, demonstrating induced lung maturation. An axiom of neonatology is that fetal stress matures the preterm lung. However, recent clinical reports indicate that the incidence of respiratory distress syndrome (RDS) is not reduced in growth-retarded infants (17), infants from preeclamptic pregnancies (18), or after prolonged preterm rupture of membranes (19). How can growth-retarded infants not be stressed sufficiently to induce lung maturation, whereas normally grown infants born at 26 wk can have mature lungs? Antenatal glucocorticoids decrease the incidence of RDS, but they seem to decrease the incidence by only 40 to 50% (20). Repetitive courses of treatment may not further decrease the incidence of RDS (21). Why are glucocorticoids not more effective even when given repetitively? We recently reported that maternal betamethasone treatments resulted in both fetal growth retardation and lung maturation, whereas fetal betamethasone treatments resulted in less lung maturation and no fetal growth retardation in sheep (22). The particularly curious aspect to the observation was that plasma betamethasone levels were 3-fold higher after fetal than maternal treatments (23).

In transgenic mice, very low fetal plasma glucocorticoid levels resulting from corticotropin-releasing hormone deficiency (CRH-/-) delayed anatomic maturation of the distal lung parenchyma with minimal effects on the surfactant system (24). However if the CRH-/- fetuses develop in CRH+/- dams or if CRH-/- dams received supplemental glucocorticoids, lung maturation proceeded normally. A very low fetal glucocorticoid level resulting from some placental transfer from dam to fetus was sufficient to sustain normal maturation. The effects of glucocorticoids on the preterm lung are confusing and complex because glucocorticoids can interfere with alveolarization while at the same time they induce structural maturation by thinning the mesenchyme and induce the surfactant system (11, 22, 25, 26). The effects depend on timing during development, dose, and certainly other factors. Interactions between glucocorticoids and cytokines are likely but have not been studied in relation to lung maturation. The bottom line is that we do not know what factors regulate normal lung maturation or what factors might optimally induce early lung maturation. Glucocorticoids are helpful, but they are only part of the story.

CYTOKINES AND LUNG MATURATION

Chronic low-grade infection/inflammation of fetal membranes and amniotic fluid is common for pregnancies that deliver very preterm (27). Histologic chorioamnionitis is associated with a decrease in RDS but an increase in BPD in one series (28). Elevated levels of the proinflammatory cytokines TNF-α, IL-1β, IL-6, and IL-8 in amniotic fluid are associated with an increased risk of BPD (29, 30). Ureaplasma urealyticum, the most common contaminant of amniotic fluid, elicits an inflammatory response in amniotic fluid and has been associated with BPD (31). These clinical observations are consistent with the interference with lung development by a proinflammatory cytokine that occurs in transgenic mice (12–15). However, cytokine effects on the developing lung need not be all bad. The proinflammatory cytokine IL-1α increased mRNA for the surfactant proteins SP-A and SP-B and improved the compliances of ventilated preterm rabbits (32). We recently found that intraamniotic endotoxin was a more potent inducer of lung maturation and the surfactant system than was betamethasone in preterm sheep (33). These observations suggest the counterintuitive hypothesis that proinflammatory cytokines can act as maturational signals in the fetus. Cytokines may have signaling roles during normal lung development as well as during lung injury and repair.

VENTILATION AND LUNG INJURY

Normal ventilation and ambient oxygen exposure may act as promoters and propagators of injury in the preterm lung. In the adult animal, ventilation with gas volumes that approach or exceed total lung capacity results in pulmonary edema and proinflammatory cytokine release in the lungs (34). Ventilation from volumes below a normal functional residual capacity also results in edema, inflammation, and proinflammatory cytokine release. Prior exposure of the isolated and perfused lung to endotoxin amplifies the ventilation-mediated injury (35). Lung gas volumes are low in preterm infants, functional residual capacities are low and unstable, and inflation is nonuniform because of surfactant deficiency (36). Modest hyperventilation of preterm lambs to PCO2 values of 25–30 mm Hg is sufficient to induce TNF-α mRNA within 2 h (M. Ikegami, unpublished data). What if the lung has been primed by exposure to antenatal proinflammatory cytokines? Routine resuscitation and the subsequent ventilation and oxygen exposure of very preterm infants may amplify lung injury after antenatal cytokine exposure.

The important concept is that the lung is just beginning to develop into a gas exchange organ over the 24–28-wk gestation interval (7, 37). Very preterm birth may result in the release of signaling molecules that can interfere with lung development. Antenatal or early postnatal inflammation may compound the adverse effects on lung development. We know very little about how the preterm fetus mounts an inflammatory response or how the fetal lung responds to inflammatory mediators. The enticing prospect is that some of the mediators are beneficial (e.g. lung maturation induced by IL-1α) and others are almost certainly detrimental (e.g. the correlations of elevated TNF-α and IL-6 with BPD) (29, 32). Deconvoluting the fetal inflammatory response and the postnatal effects of proinflammatory mediators on the lungs should yield new strategies to improve outcomes for preterm infants. Another major benefit will be new knowledge about the process of alveolarization of the lung—insights into the pathophysiology of the new BPD.