An understanding of lung development and maturation is central to the care of preterm infants because lung function is so critical to survival of the preterm. Pattle and Clements first noted the presence of surfactant in pulmonary edema foam and lung extracts. In 1959, Avery and Mead then correlated respiratory failure with decreased surfactant levels in saline extracts from the lungs of infants with respiratory distress syndrome (RDS).2 Once the association between atelectasis with hyaline membranes and surfactant levels was appreciated, a large international research effort was focused on the surfactant system. The first direct clinical benefit was the development in 1971 of the lecithin-sphingomyelin (L-S) ratio, using amniotic fluid to predict lung immaturity and the risk for RDS in preterm infants by Gluck and colleagues.24 Phosphatidylglycerol was identified for lung maturity testing in 1976 by Hallman and colleagues.29 The induction by Gregory and colleagues of continuous positive airway pressure to maintain functional residual capacity (FRC) for infants with RDS was the first application of the respiratory physiology of RDS to improve outcomes.27 Liggins and Howie first reported a decreased incidence in RDS with maternal corticosteroid treatments in 1972.49 The feasibility of surfactant treatment for lung immaturity was demonstrated in animal models in the 1970s, primarily by Enhörning and Robertson,65 and surfactant was successfully used in humans by Fujiwara and colleagues in 1980.23 This research resulted in the development of perhaps the two most effective treatments for RDS in neonatology—antenatal corticosteroids and postnatal surfactant. This progress in the application of research to the pulmonary care of the infant is continuing as molecular and cell biologic observations improve the general understanding of lung development. A major interest for the future is the prevention of bronchopulmonary dysplasia (BPD) in infants who are very preterm. The lung first appears as a ventral bud off the esophagus just caudal to the laryngotracheal sulcus.11 The grooves between the lung bud and the esophagus deepen, and the bud elongates within the surrounding mesenchyme and divides to form the main stem bronchi (Figure 70-1). Subsequent dichotomous branching gives rise to the conducting airways. The branching of the endodermal endothelium is controlled by the underlying mesenchyme because removal of the mesenchyme stops branching. Transplantation of the mesenchyme from a branching airway to more proximal airway structures induces budding in the new location. The commitment of endodermal cells to epithelial cell lineages requires the expression of families of transcription factors that include thyroid transcription factor-1, forkhead gene family members, and others.74 At least 15 homeobox domain-containing genes (HOX genes) also contribute to lung morphogenesis. Multiple other growth and differentiation factors, such as retinoic acid and the fibroblast growth factor family members (FGF)-7 and FGF-10 and their receptors are temporally and spatially expressed and are critical to early lung morphogenesis and subsequent development. Genetic ablation of these transcription and growth factors, among others, causes lung developmental abnormalities that range from tracheoesophageal fistula and altered branching morphogenesis to severe lung hypoplasia and complete aplasia of the lungs. Lobar airways are formed by about 37 days, with progression to segmental airways by 42 days and subsegmental bronchi by 48 days in the human fetus. The pulmonary vasculature branches off the sixth aortic arch to form a vascular plexus in the mesenchyme of the lung bud. Major regulators of vascular development are vascular endothelial growth factor and its receptors in the mesenchyme. Vascular development additionally requires extracellular matrix (fibronectin, laminin, type IV collagen) and other growth factors such as platelet-derived growth factor. The pulmonary artery can be identified by about 37 days, and venous structures appear somewhat later. Abnormalities in early lung embryogenesis cause tracheoesophageal syndromes, branching morphogenesis abnormalities, and aplasia. The 15 to 20 generations of airway branching occur in the pseudoglandular period of lung development from about the seventh to the eighteenth week, when airway branching is complete (Figure 70-2). The developing airways are lined with simple cuboidal cells that contain large amounts of glycogen. Neuroepithelial bodies and cartilage appear by 9 to 10 weeks. Ciliated cells, goblet cells, and basal cells are in the epithelium of proximal airways by 13 weeks. In general, epithelial differentiation is centrifugal in that the most distal tubules are lined with undifferentiated cells with progressive differentiation of the more proximal airways. Regulators of branching morphogenesis are FGF-10 and FGF-7 as well as endothelial growth factor, transforming growth factor-α, and other growth factors.68 Upper lobar development occurs earlier than lower lobe development in animals, and a similar pattern of development probably occurs in humans. Early in the pseudoglandular stage, the airways are surrounded by a loose mesenchyme with the developing vasculature and capillaries. Pulmonary arteries grow in conjunction with the airways, with the principal arterial pathways being present by 14 weeks. Pulmonary venous development occurs in parallel but with a different pattern that demarcates lung segments and sub-segments. By the end of the pseudoglandular stage, airways, arteries, and veins have developed in the pattern corresponding to that found in the adult. The canalicular stage between 16 and 25 weeks’ gestation represents the transformation of the previable lung to the potentially viable lung that can exchange gas (Figure 70-3).77 The bronchial tree has completely branched, and respiratory bronchioles are forming. The three major events during this stage are the appearance of the acinus, epithelial differentiation with the development of the potential air-blood barrier, and the start of surfactant synthesis within recognizable type II cells.11 The acinus in the mature lung is the tuft of about 6 branching generations of respiratory bronchioles, alveolar ducts, and alveoli originating from a terminal bronchiole (see Figure 70-2). This saccular branching is the critical first step for the development of the future gas exchange surface of the lung. The mesenchyme surrounding the airways becomes more vascular and more closely approximated to the airway epithelial cells (Figure 70-4). Capillaries initially form as a double capillary network between future airspaces and subsequently fuse to form a single capillary. With fusion of the vascular and epithelial basement membranes, a structure comparable to the adult air-blood barrier forms. If the double capillary network fails to fuse, the infant will have severe hypoxemia resulting from alveolar-capillary dysplasia. The total surface area occupied by the air-blood barrier begins to increase exponentially toward the end of the canalicular stage, with a resultant fall in the mean wall thickness and an increased potential for gas exchange. Epithelial differentiation is characterized by proximal to distal thinning of the epithelium by transformation of cuboidal cells into thin cells that line tubes. The tubes grow both in length and in width with attenuation of the mesenchyme, which is simultaneously becoming vascularized. During the canalicular stage, many of the cells would best be characterized as intermediary cells because they are neither mature type I nor type II epithelial cells.11 These epithelial cells develop attenuated extensions as well as some characteristics of mature type II cells such as lamellar bodies, supporting the concept that type I cells are derived from type II cells or intermediary cells that then further differentiate into type I cells. After about 20 weeks in the human fetus, cuboidal cells rich in glycogen begin to have lamellar bodies in their cytoplasm. The transcription factors TTF-1, FOXa1, FOXa2, and GATA 6 mediate type II cell differentiation.74 The glycogen in type II cells provides substrate for surfactant synthesis as the lamellar body content increases. In the adult human lung, the thin type I cells occupy about 93% of the alveolar surface versus 7% for type II cells.17 About 8% of lung cells are type I cells and about 16% of lung cells are type II cells. The saccular stage encompasses the period of lung development during the potentially viable stages of prematurity from about 24 weeks to term. The terminal sac or saccule is the developing respiratory bronchiole or alveolar duct that is elongating, branching, and widening prior to the initiation of alveolarization at about 32 weeks in the fetal human lung. Alveolarization is initiated from these terminal saccules by the appearance of septa in association with capillaries, elastin fibers, and collagen fibers (see Figure 70-4). Shallow alveolar structures with crests (or septa) with elastin at the free margin of the crests can be identified by 28 weeks’ gestation in the human.32 Alveolar numbers increase rapidly from about 32 weeks’ gestation to term when the human lung contains between about 50 and 150 million alveoli.32,47 For comparison, the adult human lung has about 500 million alveoli.60 The most rapid rate of accumulation of alveoli occurs between 32 weeks’ gestational age and the first months after term delivery (Figure 70-5). The potential lung gas volume and surface area increases from about 25 weeks’ gestation to term. This increase in lung volume, and the surface area of sacculi establishes the anatomic potential for gas exchange and thus for fetal viability. There is a wide range of lung volumes and surface areas at a given gestational age. Therefore, the gas exchange potential of different fetuses at the same gestational age will be determined in part by the structural development of the lung. Human newborns born at 22 or 23 weeks’ gestation can have a sufficiently mature lung structure to support gas exchange, indicating that structural lung maturation can be induced at very early gestational ages. Since antenatal corticosteroids increase survival at these early gestational ages, their use must support this early gestational potential for gas exchange.13 Alveolarization progresses rapidly from late fetal to early neonatal life. The traditional view was that alveolar development was completed by early childhood and that new alveoli do not develop in adults. Recent evidence in rats using 3-D visualization with high-resolution synchrotron radiation x-ray tomographic microscopy demonstrated that new alveoli continued to be formed well into adulthood.67 Using hyperpolarized helium MRI, Narayanan et al. demonstrated that alveolar formation continues until at least 20 years of age.56 This potential for continued alveolar growth explains why many preterm infants with interrupted lung development at birth can have relatively good lung function later in life.22 A number of factors that can stimulate or interfere with alveolarization have been identified (Box 70-1).45 Chronic mechanical ventilation of preterm animals using modest tidal volumes and low oxygen exposures interrupts both alveolarization and vascular development (Figure 70-6).15 Mechanical ventilation of the saccular lung disrupts elastin at the developing crests and induces an “arrest in development” characterized by lack of secondary crest formation and resulting in fewer and larger alveoli without much fibrosis or inflammation (Figure 70-7).7 Preterm infants who have died after long-term ventilation or after the development of bronchopulmonary dysplasia (BPD) also have decreased alveolar numbers and an attenuated microvasculature with less prominent airway injury and fibrosis than in the past.5 Factors that likely contribute to this arrest of lung development include many of the components of care of preterm infants. Antenatal glucocorticoid treatments in monkeys and sheep cause thinning of the interstitium and an increased surface area for gas exchange with delayed alveolar septation. Postnatal glucocorticoid treatments of the saccular lung also interrupt alveolarization and capillary development. Hyperoxia or hypoxia and poor nutrition can interfere with alveolarization. In transgenic mice, overexpression of proinflammatory mediators in the pulmonary epithelium interferes with alveolar development. Antenatal lung inflammation associated with chorioamnionitis in sheep causes delayed alveolar and microvascular development.76 Thus, multiple factors may contribute to delayed alveolarization in preterm infants. Because lung growth following the completion of alveolarization is by increase in airway and alveolar size, any event that decreases alveolar number could impact lung function as the individual ages. However, the growth potential of the human lung is remarkable, and infants with mild BPD had normal alveolar numbers at 10 to 14 years of age as estimated by hyperpolarized helium MRI.55 The residual lung structural abnormalities in the lungs of infants who have survived severe BPD remain to be characterized. The fetal airways are filled with fluid until delivery and the initiation of ventilation. Most of the information concerning quantitative aspects of fetal lung fluid is from the fetal lamb with sonographic and pathologic correlates available for the human. The fetal lung close to term contains enough fluid to maintain the airway fluid volume at about 40 mL/kg of body weight, which is somewhat larger than the FRC once air breathing is established.50 The composition of fetal lung fluid is unique relative to other fluids in the fetal sheep and most other mammalian species.37 The chloride content is high (157 mEq/L), whereas the bicarbonate and protein contents are very low. In contrast, the bicarbonate and chloride concentrations in fetal lung fluid from the rhesus monkey are not different from plasma values, demonstrating species differences in ion composition of fetal lung fluid. The electrolyte composition is maintained by transepithelial chloride secretion with bicarbonate reabsorption. Fetal lung fluid contains little protein because the fetal epithelium is quite impermeable to protein. Active transport of Cl– from the interstitium to the lumen yields a production rate for fetal lung fluid of 4 to 5 mL/kg per hour. Assuming the fetus is 3 to 4 kg, the daily production of fetal lung fluid is about 400 mL per day. Fetal lung fluid flows intermittently up the trachea with fetal breathing movements, and some of this fluid is swallowed while the rest mixes with the amniotic fluid. The pressure in the fetal trachea exceeds that in the amniotic fluid by about 2 mm Hg, maintaining an outflow resistance and the fetal lung fluid volume. The secretion of fetal lung fluid seems to be an intrinsic metabolic function of the developing lung epithelium because changes in vascular hydrostatic pressures, tracheal pressures, and fetal breathing movements do not greatly alter fetal lung fluid production rates. Although normal amounts of fetal lung fluid are essential for normal lung development, its clearance is equally essential for normal neonatal respiratory adaptation.59 Fetal lung fluid production can be completely stopped at term by vascular infusions of epinephrine at concentrations that approximate the levels of epinephrine present during labor. The epinephrine-mediated reversal of fetal lung fluid flux from secretion to reabsorption does not occur in the preterm lung. However, epinephrine-mediated clearance can be induced by pretreatment of fetal sheep with the combination of corticosteroid and triiodothyronine. Inhibition of prostaglandin synthesis with indomethacin in the fetus reduces the production of fetal lung fluid and urine. Fetal lung fluid production and volumes are maintained in the fetal sheep until the onset of labor. During active labor and delivery, fetal lung fluid volumes decrease, leaving about 35% of the fetal lung fluid to be absorbed and cleared from the lungs with breathing. Most of the fluid moves rapidly into the interstitial spaces and subsequently into the pulmonary vasculature, with less than 20% of the fluid being cleared by pulmonary lymphatics. The clearance of the fluid from the interstitial spaces occurs over many hours. Fluid clearance after birth results from active sodium transport via the epithelial sodium channel (ENaC), which can be blocked with amiloride33 (see Chapter 44). Genetic ablation of the subunit of the ENaC causes death in newborn mice because fetal lung fluid is not cleared from the lungs. Glucocorticoids upregulate the messenger RNA (mRNA) for the ENaC subunits in the fetal human lung. Transient respiratory difficulties in many infants result from delayed clearance of fetal lung fluid. Pulmonary hypoplasia is a relatively common abnormality of lung development, with a number of clinical associations and anatomic correlates.48 Primary pulmonary hypoplasia is unusual and is likely caused by abnormalities of the transcription factors and growth factors that regulate early lung morphogenesis, such as thyroid transcription factor-1 and FGF family members.74 Severe forms of acinar aplasia that probably result from abnormal regulation of lung growth and development have been reported. Secondary pulmonary hypoplasia is associated with either a restriction of lung growth or the absence of fetal breathing (Box 70-2). Any reduction of the chest cavity by a mass, effusion, or external compression can impact lung growth. Lung hypoplasia can be minimal or severe. Severe pulmonary hypoplasia associated with renal agenesis and prolonged oligohydramnios is characterized by a decrease in lung size and cell number together with narrow airways, a delay of epithelial differentiation, and surfactant deficiency. Relatively short-term oligohydramnios caused by ruptured membranes in the sixteenth to twenty-eighth week of gestation also can result in pulmonary hypoplasia, the magnitude in general correlating with the severity and length of the oligohydramnios. Infants with congenital diaphragmatic hernia have more severe hypoplasia on the ipsilateral side than on the contralateral side, although the contralateral lung also may be hypoplastic. The lungs have fewer and smaller acinar units, delayed epithelial maturation, and an associated surfactant deficiency. In experimental models, tracheal occlusion in late gestation can reverse much of the pulmonary hypoplasia resulting from diaphragmatic hernia, but the occlusion induces a decrease in type II cells and surfactant deficiency.42 The sentinel immune cells of the lung are alveolar macrophages. In adult humans and animals these cells are located in the airspaces directly in contact with the alveolar hypophase. Alveolar macrophages derived from monocytes from the circulation take residence in the lung. Local cues and growth factors including GM-CSF and the transcription factor PU.1 differentiate these monocytes to alveolar macrophages.54 Once differentiated, alveolar macrophages do not recycle and have a relatively long life span under normal conditions. Important functions of alveolar macrophages include immune surveillance, phagocytosis of invading microorganisms, antigen presentation, interactions with adaptive immune cells, and surfactant homeostasis. Fetuses do not normally have alveolar macrophages. In mice, macrophages can be detected in the lung interstitium from early gestation,6 whereas in other species including nonhuman primates and sheep, very few macrophages are found in the fetal lung.44 In all species, alveolar macrophages begin populating the lung in large numbers postnatally with the onset of air breathing. Exposure to chorioamnionitis—an infection in the amniotic fluid and fetal membranes—can mature the lung macrophages and stimulate their migration into the fetal alveolar spaces.44 Surfactant recovered from lungs of all mammalian species by alveolar wash procedures contains 70% to 80% phospholipids, about 10% protein, and about 10% neutral lipids, primarily cholesterol (Figure 70-8). The composition of the phospholipids in surfactant is unique relative to the lipid composition of lung tissue or other organs. About 60% of the phosphatidylcholine species are saturated, meaning that both fatty acids esterified to the glycerol phosphorylcholine backbone are predominantly the 16-carbon saturated fatty acid, palmitic acid. Most other phosphatidylcholine species in surfactant have a fatty acid with one double bond in the 2 position of the molecule. Saturated phosphatidylcholine is the principal surface-active component of surfactant and can be used as a relatively specific probe of surfactant metabolism. The acidic phospholipid, phosphatidylglycerol, is present in surfactant in small amounts that vary between 4% and 15% of the phospholipids in different species (Table 70-1). Surfactant phospholipids from the immature fetus or newborn contain relatively large amounts of phosphatidylinositol, which then decrease as phosphatidylglycerol appears with lung maturity.29 Phosphatidylglycerol in amniotic fluid can be measured as a test for lung maturity. The surfactant from the preterm lung is qualitatively inferior relative to surfactant from the mature lung when tested for in vivo function than is surfactant from term newborns.39 TABLE 70-1 Changes in Surfactant with Development
Lung Development and Maturation
A Brief History
Lung Structural Development
Embryonic Period
Pseudoglandular Stage
Canalicular Stage
Saccular and Alveolar Stages
Fetal Lung Fluid
Pulmonary Hypoplasia
Alveolar Macrophages
Surfactant Metabolism
Composition
Variables
Immature Lung
Mature Lung
Type II Cells
Glycogen lakes
High
Gone
Lamellar bodies
Few
Many
Microvilli
Few
Many
Surfactant Composition
Sat PC/Total PC
0.6
0.7
Phosphatidylglycerol (%)
<1
10
Phosphatidylinositol (%)
10
2
Surfactant protein A (%)
Low
5
Surfactant Function
Decreased
Normal 
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Lung Development and Maturation
