Alterations to bronchi and bronchioli during the distinct phases of human intrauterine development, at birth, or in infancy may predispose people to the later development of airflow limitation. Both genetic and exogenous factors, such as fetal or neonatal passive exposure to tobacco smoke, viral lower respiratory tract infection, prematurity, or neonatal mechanical ventilation, may influence development.
This synopsis considers the key differences between large and small airways of the human lung and their development. A more detailed consideration of the structural and biochemical changes associated with lung development is provided elsewhere (1-4). The end point for airway and lung development is a gas-exchanging organ in which air and blood come into intimate contact over a large surface area that maintains communication with the exterior. An oxygen uptake of up to 3 L/min is facilitated by an air-blood contact area approximately half the size of a singles tennis court (approximately 80 m2). The barrier separating air and blood is only 0.2 μm thick—1/50 the thickness of a sheet of airmail paper.
The respiratory region's communication with the exterior is afforded by a system of asymmetric, dichotomously branching tubes that extend peripherally to the visceral pleura from the larynx and trachea. Airways are usually designated by structure and order of division: those distal to the trachea with cartilage in their walls are bronchi. In the trachea, supportive cartilage is present in the form of irregular, sometimes branching, rings (16–20 in humans), all of which are incomplete dorsally, where they are bridged by connective tissue and bands of smooth muscle. In large bronchi the cartilages are irregular in shape but frequent enough to be found in any plane. In small bronchi, they are less frequent and may be missed in transverse section. Airways distal to the last cartilage plate are termed bronchioli. The last bronchiolar divisions have their ciliated epithelium lining interrupted by alveoli and are referred to as respiratory bronchioli; the generation proximal to the first-order respiratory bronchioles are referred to as terminal bronchioli. Terminal bronchioli form the last purely conductive airways, and the respiratory bronchiolus is the site where gaseous exchange begins. There are generally three orders of respiratory bronchioli. A single terminal bronchiolus with its succeeding respiratory bronchioli and two to nine orders of alveolar ducts and alveolar sacs together form the respiratory acinus, which is about 1 cm in diameter and forms the basic respiratory unit of the lung. Detailed differences between large and small airways have been published previously (5-7). In general, airway epithelium becomes thinner more peripherally, and cilia become shorter and more sparse than in large airways. Bronchial epithelium contains about 6,000 mucus-secreting goblet cells (Figure 1) per mm2 of surface. These goblet cells and basal cells are rarely found in bronchioli (5, 6), where nonciliated Clara cells (Figure 2) are the main secretory and stem cell. In contrast, basal and goblet cells form the stem cell of the large airway. Submucosal glands are present wherever there is cartilage.
Following the embryonic period, which in humans is the first few weeks after fertilization, four overlapping phases of lung development are recognized (Figure 3).
Pseudoglandular phase. This phase, when the preacinar branching pattern of airways and blood vessels is established, occurs from 5 to approximately 17 wk of gestation (7).
Canalicular phase. During this phase, which occurs at 16–26 wk of gestation, vascularization of peripheral mesenchyme rapidly increases, capillaries move into close contact with the surface epithelium, and connective tissue components are reduced to a minimum.
Terminal sac (saccular) phase. This phase begins about 24– 36 wk and continues until term, when additional respiratory airways develop and the future respiratory units (or acini) differentiate.
Alveolar phase. This runs from about 36 wk to term and continues for at least the first 3 yr of postnatal life, during which alveoli multiply greatly in number.
These times are approximate and vary among individuals. In other species, the proportion of gestation that each phase occupies differs (8).
The airways of the lung begin their development 22–26 d after fertilization as a ventral diverticulum budding from the foregut and lined by epithelium of endodermal origin. Normal airway branching requires both epithelium and mesenchyme. If the mesenchyme is stripped away, the airway tube will elongate but not divide (9). Conversely, mesenchymal tissue taken from an area of active branching will promote branching of epithelial tubes from an area where branching was previously complete. Branching is dependent upon interactions among cell substrate adhesion molecules, intercellular adhesion molecules, and the extracellular matrix proteins, particularly proteoglycans and glycosaminoglycans. In humans, the lobar and segmental bronchi appear at about the 5th week. Division of intrasegmental airways is fastest (particularly in the right lung) between the 10th and 14th wk, by which time about 70% of the airway generations present at birth have formed (10). The extension of the airway tubes is due to rapid proliferation of their epithelial lining cells: cell division occurs particularly at the ends of the tubes, the so-called bronchial buds. Branching points are determined by interactions with surrounding mesenchyme, and buds usually (but not always) form daughter branches by irregular dichotomy, thereby doubling the number of airway branches with each division. The pattern of airway branching is complete by about the 16th wk of intrauterine life. So, while airway size obviously changes after birth, the pattern of branching does not; the airways of the newborn lung are essentially the adult in miniature (11). After airway branching is complete, the airways continue to increase in size as lung volume increases. From 22 wk of gestation until birth there is a linear increase in diameter in all airways from the bronchus to the terminal bronchiole. This growth continues after birth: airways double or triple in diameter and length between birth and adulthood (12). The ultimate size of the airways does not appear to be affected by premature delivery. The number of terminal bronchioles, which form the last purely conductive airways, is estimated at 25,000 in the adult.
Relative to their more proximal divisions, peripheral conducting airways are large in diameter at 1–3 mo of age, attaining their normal adult relative size after 1 yr (13). However, small airways in children are reported to contribute more to total resistance to airflow than they do in the adult (11, 14).
In humans, four cell types compose the surface epithelium of proximal airways: (1) ciliated, (2) mucus-secreting (goblet), (3) indeterminate, and (4) basal cells. In terminal bronchioli, a fifth cell is found interspersed between ciliated cells: the Clara cell, which is a highly metabolic, secretory, and stem cell form. Ciliated cells are present throughout the respiratory tract, as far peripherally as the respiratory bronchioli. Peptide-producing neuroendocrine cells with characteristic dense-cored granules (DCG cells) may occur singly or in groups, often innervated. Their number and predominant location with the airway tree vary with lung development and growth. All airway epithelial cells develop by differentiation and maturation of primitive endodermal cells. With advancing gestation the process of differentiation follows a centrifugal pattern; i.e., maturation begins in proximal (large) airways and spreads distally. The timing of the main cellular events is shown in Figure 4. During the late embryonic/early pseudoglandular phase, the epithelial lining is stratified and consists of vertically orientated cells with their thinner ends extending to more basally situated cells (8, 16). At this early stage the tracheal lining closely resembles that of the developing esophagus.
Differentiation of a ciliated epithelium is apparent between 11 and 16 wk of gestation in man, at the end of the pseudoglandular phase, when the number of bronchial tubes has increased significantly and mesenchyme has already begun to differentiate into cartilage and bronchial smooth muscle. Cilia develop from centrioles, which arise either directly by division of pre-existing centrioles (as in the formation of primary or rudimentary cilia) or indirectly by a sequence of events initiated in the Golgi region, beginning with fibrogranular aggregates from which arise deuterosomes and a generative complex of precentrioles (8, 17, 18).
The presence of intracellular mucus has been demonstrated histochemically in human fetal lung at 13 wk of gestation (10, 16); such cells are sparse and located within crypts of corrugated surface epithelium or in newly forming submucosal glands. Presecretory cells appear at about the same time as preciliated cells. Two types of secretory granule may be identified by electron microscopy: electron-dense and electron-lucent. Three types of cell may also be found: (1) those with only electron-dense serous granules (Figure 5), (2) those with only electron-lucent mucous granules, and (3) those with a mixture of the two. The three cell types probably correspond to the three histochemically distinct types seen by light microscopy after Alcian blue (pH 2.5) and periodic acid–Schiff (PAS) stains used in combination: (1) PAS-positive (pink), (2) Alcian blue–positive (blue), and (3) heliotrope (mixed). By 22 wk of gestation, goblet cells are found as far as the distal ends of large bronchi. The number of goblet cells peaks at midgestation, when they represent 30–35% of cells lining the luminal surface. Toward the end of gestation there is a relative decrease in their number, so that they are less frequent than in the adult (19). With increasing gestational age they extend more peripherally, and by term they are even reported in bronchioli (12).
The proportion of goblet to ciliated cells increases rapidly in the first 4 wk after birth, particularly in premature infants, who have a greater number than normal for their postconceptional age and the size of their airways (12).
The nonciliated bronchiolar, or Clara, cell is thought to develop during the second half of gestation from primitive glycogen-containing nonciliated cells of the terminal airways (Figure 6). By 16–17 wk of gestation, the dome-like apical protrusion that is characteristic of the mature cell has formed. Maturation involves gradual loss of cytoplasmic glycogen, increasing ribosomal content, and the appearance of electron-dense secretory granules, which may become numerous by 24 wk of gestation (20). In the adult human lung, a low-molecular-weight antileukoprotease can be localized to serous cells of submucosal glands, surface goblet cells, and bronchiolar Clara cells (21). Recently, this antiprotease has been identified in the human trachea, in submucosal glands, as early as the 16th wk of fetal life and has been shown to be present in bronchiolar epithelium (presumed to be in Clara cells) by the 36th wk of gestation (22). These data argue for early appearance of a protective antiprotease screen and the maturation of Clara cells at a time relatively late in gestation but before parturition.
Neuroendocrine or DCG cells (Figure 7) are reported to be the first type to differentiate and mature within primitive airway epithelium. Distributed singly or in pairs, they are identified at 8 wk of gestation (23, 24). They are weakly argyrophilic and show immunoreactivity for serotonin and neuron-specific enolase (25) but not, as yet, for bombesin and other peptides. Bombesin-like immunoreactivity and serotonin positivity are found at about 10 wk of gestation, at a time when submucosal nerves and ganglia react for neuron-specific enolase (24). At the end of gestation, there is an increase in DCG cells and neuroepithelial bodies in peripheral airways (24).
The basal cell is the last major cell type to mature and is restricted to large airways. By light microscopy, basal cells have been reported in the trachea of 10-wk-old fetuses. However, by electron microscopy and immunocytochemistry, the only basally located cells identified at this time are DCG cells and undifferentiated cells rich in glycogen. By 12 wk of gestation, the immunoreactivity of epidermal keratin (a marker of maturation for the basal cell type) is weakly positive and electron microscopy shows basally located cells containing tonofilaments, well-developed desmosomes, and some hemidesmosomes, the last attaching basal cells to the epithelial basement membrane (20). Fully mature basal cells are not identifiable until the canalicular and saccular stages of development.
Intraepithelial leukocytes resembling lymphocytes in morphology are found in the basal zone of the epithelium by 16 wk of gestation in humans and immediately before birth in rats. Occasionally they appear to contain a few electron-dense granules similar to those characteristic of large, granular lymphocytes. Mast cells (and the related intraepithelial globular leukocytes of the rat) are found in normal adult airway epithelium but have not been described in the fetus.
In the adult human trachea and bronchi there are numerous glands. Each gland is tubuloacinar, with a duct opening into and continuous with the airway lumen. Submucosal glands are responsible for producing most of the mucus found in the large airways. They are present wherever there is cartilage, located mainly in the submucosa between the cartilage and the surface epithelium. In the normal adult the area occupied by gland constitutes about 12% of the wall. In children the area is increased to about 17% (26). This difference led Field (27) and Matsuba and Thurlbeck (26) to suggest that mucous gland hypertrophy might be a more significant change in children than in adults.
Airway submucosal glands first appear in the human trachea as early as 10 wk of gestation. They develop progressively outward and reach the main carina some 7 d later (28). In bronchi, they are present by the 4th mo of fetal life. in greatest concentration proximally, decreasing peripherally, and especially concentrated at airway bifurcations (29). In the main extrapulmonary bronchi, the rate of gland formation reaches a peak during the 12th to 14th fetal wk, decreasing after this time and terminating during the middle of the 23rd wk of gestation. It has been estimated that at this time some 4,000 glands are present in the trachea, the highest density now in the cartilaginous (i.e., anteriolateral) wall (28, 29). Few new glands are formed in childhood; an increase in gland area associated with childhood and hypersecretory conditions is the result of an increase in gland complexity rather than gland number per se.
At 6–8 wk of gestation, airway smooth muscle cells appear in the trachea and main and lobar bronchi. Muscle then develops sequentially along segmental, terminal, and respiratory bronchioles and alveolar ducts. The human fetal airway smooth muscle contracts spontaneously in the first trimester; it also responds to pharmacologic manipulation (30). During fetal life and childhood there is an increase in the amount of bronchial smooth muscle relative to the size of the airways. The bronchial smooth muscle at birth has a mature structure (31), is innervated (32), and has been shown to contract. Airway reactivity to methacholine, reversible with metaproterenol, is demonstrable in normal infants (33). About 3% of the bronchial wall is occupied by bronchial smooth muscle in both the child and adult, whereas in bronchioli it is 20% of the wall in the adult and only 10% in the child (26). Examination of airways in full-term and premature babies suggests that there is a more rapid increase in the amount of bronchial smooth muscle immediately after birth, probably as a result of transition to air breathing. This means that premature babies have a larger amount of muscle than normal for both their postconceptional age and their airway size. Babies who are ventilated artificially after birth have an even larger amount of muscle (12, 34). Postinfective bronchiolitis also abnormally increases the proportion of the bronchiolar wall occupied by smooth muscle.
Cartilage first appears in the 4th gestational wk in the trachea, the 10th wk in the main bronchi, and the 12th wk in segmental bronchi. Cartilage continues to form peripherally until about 2 mo after birth. After this time there is little further extension, but there is a progressive increase in the total cartilage mass throughout infancy and childhood.
Extracellular matrix provides structural support as well as influencing morphogenesis. Excessive increase has been reported in cases of bronchopulmonary dysplasia and respiratory distress of the newborn (35, 36). The lungs of these patients had higher concentrations of DNA, hydroxyproline, and desmosine than control infants.
From the ectoderm, the neural plate and associated neural crest develop autonomic nerves that migrate to supply pulmonary effector structures (37). Migrating neural-crest cells take up positions in the walls of the future trachea and lung buds before the trachea separates from the esophagus (4–5 wk of gestation). By 6 wk, the essential anatomical features of the sympathetic and parasympathetic systems are established.
Ganglia appear in extrachondrial tissue of the trachea by 7 wk of gestation and extend to second-generation bronchi. Innervation of major arteries and veins begins at 10 wk of gestation. By 16 wk, growth in the trachea results in a well-defined posterior plexus and an inner plexus between cartilage and epithelium with nerve fibers extending to submucosal glands and tracheal muscle. At this time, ganglia are seen along the extrachondrial and inner plexuses at bronchial bifurcations and adventitia down to small bronchi.
At birth the distribution and number of nerves to all airway structures is similar to that in the adult, with sympathetic and parasympathetic nerve fibers extending as far as the alveolar ducts (32). The number and type of neuropeptides within the nerves changes with age. The total number of neuropeptide-containing nerves, mainly bronchodilators, decreases in the respiratory region after age 3 yr (32). The bronchoconstrictor response to histamine and methacholine also appears to decrease with age.
Nerve trunks also supply the preacinar blood vessels running in the vascular adventitia. The neuropeptides in these nerves may have a trophic effect on the vascular smooth–muscle cells (38). In infants with pulmonary hypertension, the increase in arterial smooth muscle is accompanied by an increase in the number of nerve fibers. The vasoactive peptides in the nerves supplying the arteries are mainly vasoconstrictors (38).
Although little is known of autonomic receptors in the developing human lung, there is evidence that they change with age (39). There are fewer β-receptors (bronchodilator) in fetal than in adult rabbits (40). In rats, β-receptors progressively increase with age from newborn, to young, to adult (41). Conversely, muscarinic receptors (bronchoconstrictor) decrease with age in the rat (42). In human fetal lung, β adrenoceptors and receptors for vasoactive intestinal polypeptide are present at 14 wk of gestation, increasing thereafter (43, 44). They are found in the surface epithelium, terminal tubules, and pulmonary arteries. Alpha-1 adrenoceptors and muscarinic receptors are not detected before 23 wk of gestation. Functional studies in humans suggest a decrease in muscarinic receptors and an increase in β adrenoreceptors in the first year of life (33).
The development of pulmonary arteries and veins is closely related to that of the bronchial tree: before birth they relate to the dividing airways and following birth, to the rapidly multiplying alveoli.
Arteries that run alongside and branch with airways are termed conventional. In addition, there are supernumerary vessels (particularly at the periphery) that do not branch with the airway but directly supply the adjacent alveoli. During development, supernumerary arteries appear (45) at the same time as the conventional; by 12 wk of gestation they are present in roughly their adult proportions, even though the full complement of airways has yet to appear and the alveoli that they will supply are not yet present. Veins develop at the same time as arteries; supernumerary veins have been identified in greater number than supernumerary arteries (46). The total adult number of preacinar conventional vessels is present by the 5th mo of intrauterine life. In later fetal life, intra-acinar arteries develop, accompanying respiratory airways and alveoli. The vessels grow in size and length, the main branches increasing more rapidly during fetal life and infancy (0–18 mo of age) than childhood.
Intrapulmonary bronchial arteries extend along the airways as the cartilage forms. In the adult the bronchial arteries extend to a level a few generations proximal to the terminal bronchioles. They divide into a capillary network that drains into the pulmonary veins, either directly or via adjacent alveoli (46, 47).
The pattern of lung development is primarily determined by the branching pattern of the airways, which in turn is greatly influenced by interaction with the surrounding mesenchyme, from which the vasculature and supportive structures derive. The controlling factors are complex and as yet little studied. That genetic factors operate is suggested by the existence of familial similarities in the pattern of arterial branching.
Factors released from the investing mesenchyme and by direct epithelial-to-mesodermal cell contact are clearly important in inducing airway division and the formation of new airway buds (48, 49). Airway branching and lung growth are influenced by a variety of factors, including hormones and growth factors, with a balance being reached between those causing multiplication of epithelial cells (e.g., insulin-like growth factor or epidermal growth factor) and those (like transforming growth factor β) that are powerful inhibitors of epithelial cell multiplication but enhance protein synthesis (50). Physical factors are also implicated in controlling lung growth. Restricted space availability, as in congenital diaphragmatic hernia, leads to a reduction in airway number (51). Fluid produced within the airway lumen is controlled by the epithelial cells and is vital to normal airway development. Drainage of fluid either experimentally or as a result of premature rupture of membranes (52) leads to hypoplastic lungs, while tracheal ligation in experimental animals or in patients with laryngeal atresia causes an increase in lung size (53, 54). Changes in the amount of amniotic fluid, as seen in oligohydramnios as a result of renal agenesis and after amniocentesis in experimental animals, leads to a reduced airway number (55, 56). Fetal breathing movements also influence the development of airways (57, 58).
Circulating and locally released factors also play an important role in alveolar multiplication; growth hormone and somatomedin have been involved experimentally. Stretch may be an important stimulus, and oxygen, calorie intake, and vitamin status have profound effects on lung growth (59, 60). Pituitary, adrenal, and thyroid hormones are implicated in controlling lung maturation, particularly the time of appearance of lamellar bodies in type II cells and the onset of increased surfactant activity, which is all-important during lung expansion at the first breath.
Respiratory movements associated with fetal “breathing” may also affect final lung weight, volume, and time of alveolar maturation (61).
The development and growth of the lung is a remarkable blend of genetic and local environmental interaction, and it is no wonder that a wide range of abnormalities may be recognized at birth or during childhood. The time before 16 wk of gestation is an important one for the development of the airway branching pattern. Prematurity and artificial ventilation at birth clearly increase the number of goblet cells and smooth-muscle mass. The structure and proportions of the infant's airways and lungs are different than that of the adult, and the relatively greater chest wall compliance of the child may accentuate the functional differences. These and a variety of other factors discussed above may also predispose some children to developing wheezing conditions and later airway inflammation and asthma or chronic obstructive airway disease.
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