Richard L. Auten
For the pediatrician, it is important to understand lung growth and development in order to properly diagnose and treat children for whom both may have gone wrong. It is crucial to the development of new diagnostic and treatment choices. This chapter will highlight the components of the developing lung, the factors that regulate their interaction, and the effects on pulmonary function in children.
Growth of the lung postnatally during infancy and childhood has typically been described in terms of the subdivision of alveoli, which accompanies the lengthening and widening of conducting airways, along with the vascular supplies for the growing bronchi and lung parenchyma.1 Investigations using animal models of mammalian lung development and disease increasingly reveal a dynamic process of lung cell turnover, repair, and regeneration with particular windows of vulnerability which will be important to pediatricians. Disrupted lung growth in early childhood has lifelong effects on lung function.2
CHILDHOOD EVENTS THAT PROGRAM ADULT LUNG FUNCTION
Students and trainees of recent vintage will doubtless have been introduced to the “Barker hypothesis,” which describes a relationship between early life events and the susceptibility to acquired disease states in adulthood. Cohort studies from England describing study subjects born 70 to 80 years ago linked the diagnosis of pneumonia before age 2 years with substantial decrements in lung function (forced expiratory volume in 1 second, abbreviated FEV1) adjusted for age and height.3 More recent reports from a similarly designed larger cohort study from England failed to demonstrate a significant association between childhood “chest diseases” such as asthma, pneumonia, and whooping cough, and an accelerated rate of decline in lung function, so the role of childhood lung infection and lung growth on later adult pulmonary function is not yet clear.4
On the other hand, premature birth, arguably a disruption of lung development at an early vulnerable period, is associated with impaired lung function in later childhood and the adult years, with significant effects on forced expiratory flows and wheezing. Structural changes in lung parenchyma observed in chest-computed tomography scans of adults who were born prematurely are common, but their functional significance is unclear.5 Disrupted alveolar development or altered capacities of repair that occur in early childhood may lower the threshold at which chronic age-related pulmonary diseases are manifested . Improved understanding of the interactions of normal lung growth and environmental exposures will be indispensable to pediatricians now and in the future who seek to protect and preserve the function of the lung with its vulnerable interface with the “outside world.”
PHASES OF LUNG DEVELOPMENT
Lung development (see Fig. 59-1) begins in embryonic life with outpouching of the tracheal primordium from foregut endoderm. Reciprocal signaling between epithelial cells lining the respiratory tract and underlying mesenchymal cells controls branching morphogenesis of the conducting airways. Toward the end of normal pregnancy, terminal respiratory saccules become lined with more flattened epithelium that will become type I pneumocytes that perform gas exchange in concert with pulmonary capillaries. Adjacent cuboidal epithelial cells in the primitive alveoli will become type II alveolar pneumocytes. Normal development of the lung during postnatal development in infancy and childhood is dominated by formation and differentiation of alveoli during the first years.
ALVEOLAR DEVELOPMENT
It has been proposed that alveolar homeostasis should be conceptualized as a functional “syncytium,” comprised of interdependent reciprocal signaling among pulmonary fibroblasts, pulmonary capillary endothelial cells, alveolar epithelial cells, and, after birth, resident alveolar macrophages (Fig. 502-1).6
Type I alveolar epithelium constitutes most of the alveolar surface area, and conducts most of the lung water trafficking through aqueporin channels necessary to keep alveoli from flooding. These epithelial cells overlie a matrix of mesenchyme-containing pulmonary fibroblasts within collagen, actin, and elastin fibers. Together with pulmonary capillaries, they form the alveolar septum, which attenuates and flattens during infancy, increasing surface area for gas exchange. Type II alveolar epithelial cells are metabolically active, synthesizing, secreting, and metabolizing pulmonary surfactant that allows alveoli to remain gas filled at the end of exhalation. These cells also appear to serve as a progenitor pool from which other type II cells and type I cells derive during development, repair, and regeneration.7 They secrete cytokines such as vascular endothelial growth factor (VEGF), which induce proliferation in neighboring capillary endothelial cells to allow extension of capillary tubes into alveolar septa during alveologenesis. Along with alveolar macrophages and bronchiolar epithelium, type II cells secrete proinflammatory cytokines and leukocyte chemokines in response to inflammatory stimuli.
The increases in lung surface area and relative reductions in alveolar size with lung growth are driven by flattening of the alveolar type I pneumocytes overlying elastin and collagen fibers in alveolar septa (Fig. 502-2). The actual number of alveoli and their rate of growth in infancy and early childhood are not precisely known, but the best available evidence suggests that additional alveoli develop at the extreme periphery of the growing lung, and that this process continues through age 2 years, with significant slowing thereafter. The specific contributions of paracrine factors from the cellular denizens of the alveolus during this stage of lung development have not been thoroughly studied.8
Alveolar repair and regeneration is believed to recapitulate alveolar growth in certain aspects. Lessons from animal models suggest that alveolar number is closely matched with metabolic demands and the size of the individual.9Surgical removal of enough lung results in compensatory increases in lung volume in the remaining lung, with generation of more alveoli, if the loss of lung occurs early in postnatal development in animal models.10 There are very limited data in humans regarding the plasticity of alveolar number during infancy and childhood. Post-transplant increases in total alveolar volume estimated by measuring functional residual capacity suggest that near normal lung growth occurs in the transplanted lung in children less than age 3 years11; this appears to depend on the age of the transplanted lung, with immature lung demonstrating greater plasticity.12
Defects or disturbances in alveolar growth are most commonly found in children prematurely born and subjected to oxidative stress and intensive care aimed at treating respiratory insufficiency. The most common syndrome is bronchopulmonary dysplasia (BPD), a term used to describe the morphologic changes seen in conducting airways at autopsy, as a sequela of respiratory distress syndrome, before the development of surfactant replacement therapy. See Chapters 59 and 513.
Modern neonatal intensive care supports survival of less mature babies, with oxidative and mechanical insults taking place at earlier stages of lung development. Modern-day bronchopulmonary dysplasia (BPD) is believed to result in fewer, larger alveoli as demonstrated in a premature baboon model designed specifically to mimic modern neonatal intensive care.13 The lifelong growth potential of alveoli in children with BPD is unclear, but some evidence suggests that individuals born prematurely are at risk for airflow limitations, as well as emphysema in adulthood.14
Intervention with antenatal glucocorticoids just before preterm delivery is an example of a medical intervention at a specific stage of lung development that has been clearly shown to “accelerate” lung development and function, reducing the incidence and severity of respiratory distress syndrome (surfactant deficiency). Glucocorticoid administration just before preterm delivery augments surfactant synthesis and secretion and interstitial elastin deposition, which mark lung maturation and support alveolar structure, and are among many pathways beneficially affected.
FIGURE 502-1. (Left) Resident cells comprising the alveolus, lined by type I epithelium with the more numerous type II epithelial cells making up relatively less of the gas- exchange surface. (Right) During the alveolar stage of development, adjacent alveolar septa undergo thinning, and become apposed with an alveolar capillary extending into the 2° septal crest, which contains more concentrated deposition of α-actin and elastin.
FIGURE 502-2. With normal growth, thoracic expansion precedes alveolar subdivision and enlargement, with parallel extension and dilation of conducting airways and accompanying blood vessels. This leads to increased gas-exchange surface that is parallel to decreased vascular and airway resistance, achieving balanced growth and function. (Adapted with permission from American Thoracic Society, Am J Resp Crit Care Med. 2004;170:319-343.)
AIRWAY GROWTH
By the time the fetus is viable, the subdivisions of conducting airways have developed. The bronchial vascular supply is independent of the pulmonary vascular supply and does not contribute to gas exchange. Conducting airways grow in length and diameter. The relationship between airway and parenchymal growth (forced expiratory volume in 1 second, FEV1/forced vital capacity, abbreviated FVC) changes with age throughout life.15 Disparities between the rates of lung and airway growth, termed dysanaptic growth, take place in certain circumstances such as bronchopulmonary dysplasia (BPD) or pulmonary hypoplasia. Male-female differences in the FEV1/FVC ratio arise in early childhood and persist.
Airway function and development during infancy and childhood can be altered by environmental (eg, air pollution and tobacco smoke) and immunologic challenges (eg, viral infection), leading to increased vulnerability to airway hyperreactivity. These effects depend on the developmental windows of vulnerability during which the perturbation was encountered. Animal studies of oxidative stress, allergen exposure, infectious exposure, and air pollutant exposure during the immediate postnatal period or during early infancy in rodents16 and primates17 show alterations of the numbers of developed airways, airway innervation, and airway smooth muscle orientation. Decrements in airflow and lung function in early childhood predict later impairments of airway function in children and adults.18 Increasing evidence links prenatal19 and childhood20 exposure to air pollutants to impaired lung function, which has important policy implications for environmental air quality limits. The precise contribution of anatomically altered conducting airways or their capacity for growth in length and diameter in children has not been thoroughly studied.
Premature newborns (with or without BPD) may demonstrate improvements in lung volume measured by pulmonary function testing, but without corresponding improvements in air flow (dysanapsis). Subnormal alveolar septal tethering of the distal conducting airways would be expected in premature newborns recovering from bronchopulmonary dysplasia, in which delayed alveolar development is a cardinal feature.
Thorough understanding of lung growth in early childhood has been limited by a relative dearth of precise measurements of pulmonary function in preschool-aged children. Relatively recent advances in and commercial availability of pulmonary function tests suited to small children have begun to fill this knowledge gap using impulse oscillometry, gas washout, plethysmography, and spirometry.21 Equally important is the establishment of normative standards by which to assess the resultant measurements. Improvements in mathematical modeling of the contributions of age, sex, height, and other variables to pulmonary function measurements will be necessary in the absence of empirical data in large numbers of preschool children of varied ethnicities.22
The effects of environmental and infectious exposures on lung function during infancy and childhood have been intensively studied in recent years, but the contribution of alterations in airway smooth muscle during this phase of life is less well understood. Studies in infant rhesus monkeys suggest that early environmental exposure to ozone and dust mites alters the number of distal airways and changes the structural orientation of distal airway smooth muscle, with a concomitant increase in allergen-provoked airway resistance.17 The recent controversy over the so-called hygiene hypothesis represents as yet unresolved questions about how early exposure to molecular patterns (eg, dust mite antigen, viral/bacterial infection, ingested food antigens) recognized by innate and adaptive immune systems programs the repertoire of inflammatory and immunologic responses in early childhood, contributing to wheezing and asthma.23
Oxidative stress at vulnerable periods during early infancy and in premature newborns may contribute to alterations in smooth muscle programming or reactivity, but anatomic data in humans is scant. Improved survival rates among premature babies with modern-day bronchopulmonary dysplasia (BPD) have left far fewer sources of autopsy material. Premature babies who developed BPD are more likely to develop wheezing than similarly premature babies without BPD, but the basis for this tendency is not well understood.14 Animal models such as the preterm sheep demonstrate increased expiratory resistance but without parallel effects on the structure of airway smooth muscle.14 There is indirect evidence that the increased tendency to wheeze in infancy among premature babies with BPD is not analogous to allergic asthma, being less clinically responsive to bronchodilators, less productive of exhaled nitric oxide (a marker of airway inflammation), and less responsive to airway challenges linked with allergic asthma.
VASCULAR DEVELOPMENT
Bronchial arteries undergo angiogenesis throughout life, in concert with overall lung growth, and do not extend into acini, so they do not take part in gas exchange. Preacinar pulmonary arterioles are divided from the main pulmonary arteries during fetal life. Further development of intra-acinar vessels parallel the growth of the adjacent alveoli (Fig. 502-2). Microvascular development of the gas exchange region of the lung takes place during infancy and early childhood, up to approximately age 3 years, although no clear delineation has been established. As the alveolar septa thin, the double capillary networks that are characteristic of human newborn lung are reduced to single capillary layers, which function in close spatial proximity to both surfaces of alveolar septum. The thinning of the septa is accompanied by apoptosis of pulmonary fibroblasts and alveolar type II epithelial cells. Expansion of the proportion of the lung occupied by capillaries takes place throughout later childhood and on into adult life.24
Direct experimental manipulation of capillary growth using strategies aimed at blocking vascular endothelial growth factor (VEGF) action interrupt alveolar development in newborn rodents, and there are associated disturbances of the ligands and receptors involved in pulmonary angiogenesis in children who succumbed to bronchopulmonary dysplasia (BPD), as well as in the baboon model of clinical BPD.25The role of vascular homeostasis in alveolar development during late infancy and early childhood remains unknown.
CONNECTIVE TISSUE
During infancy, the conducting airways are relatively compliant, with cartilage support of the trachea and mainstem bronchi. Smaller airways develop cartilaginous support mainly after birth and become progressively less compliant over the first few years. Connective tissue surrounds the bronchi and contains lymphatic channels that drain pulmonary acini. The elastic elements within lung parenchyma (elastin, type IV collagen) which confer tensile strength to the lung are rudimentary at birth, rendering the neonatal lung relatively more vulnerable to over distension and mechanical injury with positive pressure ventilation.
The connective tissue scaffold, which develops during fetal life and during infancy, delimits the alveolar architecture. Plasticity of the mesenchyme can result in the differentiation of epithelial cells that comprise future alveoli, but this appears to be limited to the early alveolar stage of development. The spatial arrangements of elastin and tropoelastin fibers appear to be critical to the tensile strength and arrangement of developing alveoli. Disordered elastin fiber arrangement is characteristic of disrupted alveolar development.26 The role of connective tissue in the regulation of alveolar regeneration during childhood is not clear, although high levels of strain do appear to be necessary to induce postpneumonectomy lung growth in adults.27
CONTROL OF LUNG GROWTH
Metabolic demands have a major influence on lung capacity in mammals, but the effects in humans are not as well defined. Hypobaric hypoxia, which affects nearly half a billion people living at altitudes exceeding 1500 m, increases thoracic volumes, vital capacities, and diffusion capacity, even in residents not native to high altitude.28 There are limited data to define the structural bases in humans. Experimental models of chronic hypoxemia in rodents show that the effects on alveolar growth depend on the stage of the exposure: Newborn alveolar development is stunted, whereas juvenile lung growth is enhanced. Consistent with these observations are studies showing that starvation in animal models and in humans can restrict the alveolar number, which is decreased in children who died with bronchopulmonary dysplasia, a condition usually accompanied by suboptimal nutrition. Restoration of nutrition in animals restores alveolar number,29 but whether nutritional repletion has similar affects on alveolar number in children during infancy and childhood is not known.
On the other hand, conditions that restrict lung expansion during fetal life, such as oligohydramnios or congenital diaphragmatic hernia, result in alveolar hypoplasia. Recovery in survivors is accompanied by some compensatory lung growth, but without complete recovery of normal lung function.30 Cellular stretch appears to be a key mechanism for mechanical signal transduction (see the section “Connective Tissue”) and alveolar development in fetal life and during infancy. The well-recognized effects of fetal breathing on alveolar development do not appear to be transduced via parenchymal nerve signals, since loss of nerve connections during the early alveolar stage of lung development does not appear to affect subsequent lung alveolar or mechanical development, at least in experimental models.
A myriad of biochemical pathways have been identified in recent years that are linked to the control of lung growth. Retinoic acid is one of the prototypical master-regulating pathways required for early airway branching in mammalian models of lung development, and serves as an example of reciprocal paracrine signaling between differentiating epithelium and subjacent mesenchyme.31 Supplemental retinoic acid has been tested in several animal models and in premature newborns at high risk to develop broncho-pulmonary dysplasia (BPD), predominantly a failure of alveolar growth with statistically significant but quantitatively modest results.32 In more mature animal models, supplementation with retinoic acid stimulates alveolar regrowth after lung injury or lung resection.
More recently, nitric oxide has been identified as a critical signaling molecule for many pathways that affect lung development, angio-genesis in particular, or to oppose pathways known to impede lung development, like inflammation. Relative “defects” in endogenous nitric oxide synthesis identified in premature and immature animals led to studies supplying exogenous nitric oxide to correct these defects, some with strikingly beneficial effects, others with more modest effects. Clinical trials supplementing inhaled nitric oxide in an effort to prevent BPD have also yielded mixed results, and this is consistent with the notion that multiple factors interact to specify lung growth and regeneration, and the defects in lung growth in infancy may not respond to a single intervention.33 In general, manipulations that block inflammatory pathways in animal models of BPD preserve alveolar development.34-36
FIGURE 502-3. Potential cell populations taking part in airway/alveolar repair: (1) variant nonciliated bronchiolar epithelial (Clara) cells; (2) bronchoalveolar “stem cells”; (3) ciliated cells that proliferate and differentiate to Clara cells; (4) Clara cells; (5) type II epithelial cell subpopulation; and (6) neuroepithelial bodies with neuroendocrine cells that self-renew but do not give rise to other cell types. (Reproduced with permission of the Company of Biologists. Rawlins and Hogan, Development. 2006; 133:2455.)
The differences between the cellular components that control lung growth during childhood, and those that regulate airway and alveolar repair during childhood and adulthood are not yet fully understood. Recent studies have focused on identifying the so-called stem cells or transit amplifying cells in the lung that serve as the population from which alveolar component cells derive.7,37 Similar studies have been focused on conducting airway epithelial cells, with the hope that improved understanding of normal growth and development in childhood can lead to therapeutic strategies that could safely regenerate damaged lung. Several potential schemes have been proposed by which epithelial repair might take place (Fig. 502-3).7
One theoretical obstacle to such an approach is local differences in the bioavail-ability of paracrine factors that control growth of lung components. These spatial inhomogeneities of cell division and differentiation could potentially contribute to dysanapsis, if there were defective development of epithelium relative to the development of pulmonary capillary development, or if airway caliber growth did not keep pace with airway lengthening. As therapeutic advances are employed at earlier stages of lung development for infants and children who suffer from impaired lung development, it will be important to prospectively evaluate lung growth and development. The stage of childhood at which therapies are introduced will very likely determine the potential for coordinated growth of lung components sufficient to achieve adequate function as children become adults.