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Publisher : Elsevier. This definitive text on respiratory disease in children has been completely updated and revised for the 7th Edition. Several new chapters have been added, including information on the impact of environmental pollution on lung disease in children. Provides the most authoritative and comprehensive coverage available of basic science and clinical problems related to pediatric lung disease. Section I. General Considerations Chapter editor listed in parentheses with chapter title. Whitsett, M.

Wert, Ph. Jobe, M. Wohl, M. West, M. Barnes, D. Wood, M. Diagnostic Imaging of the Respiratory Tract Bush -? Olsen, Ph. Owens, B. Castile, M. Cooper, M. Stark, M. Colasurdo, M. Dobyns, M. Carpenter, M. Durmowicz, M. Stenmark, M. Noyes, M. Coates, M. Section II. Respiratory Disorders in the Newborn Chitty, Ph. Nicholson, D. Cantab , M. Bronchopulmonary Dysplasia Chernick - Steven H.

Abman, M. Davis, M. Nogee, M. Section III. Disorders of the Pleura Section IV. Infections of the Respiratory Tract Papadopoulos, M. Johnston, M. Balfour-Lynn, M. Davies, M. Bronchitis Chernick - Gerald M. Loughlin, M. Brochiolitis Chernick - Mary Ellen B. Viral Pneumonia Boat - James E. Crowe, Jr. Cauduro Marostica, M. Stokes, M.

Bronchiectasis Chernick - Anne B. Chang, Ph. Redding, M. Section V. Influenza Boat - Margaret W. Leigh, M. Barry Seltz, M. Barton, M. Hons and Ellis K. Hon, M. In: Fetus, Newborn, Child, and genes during gastrulation and axial pattern formation in the mouse embryo. Am Rev Respir Dis ;— Hilfer SR: Development of terminal buds in the fetal mouse lung.

Associate Professor Anne Chang

Scanning Annu Rev Chi EY: The ultrastructural study of glycogen and lamellar bodies in the Physiol ;— Exp Lung Res ;— Anat Embryol ;— J Biol Chem Ballard PL: Hormonal regulation of pulmonary surfactant. Endocr Rev Scarpelli EM: Lung cells from embryo to maturity. In: Scarpelli EM, ed: ;— Pulmonary Physiology.

Fetus, Newborn, Child, and Adolescent, 2nd ed. Annu Rev Physiol ;— Thurlbeck WM: Pre- and postnatal organ development. In: Chernick V, Am J Obstet Gynecol ;— Cellular and Integrative. Philadelphia: BC Decker, , pp 23— Yeomans ER: Prenatal corticosteroid therapy to prevent respiratory distress Burri PH: Structural aspects of prenatal and postnatal development and syndrome. Semin Perinatol ;— Jobe AH: Antenatal factors and the development of bronchopulmonary 1st ed. New York: Marcel Dekker, , p 1. Semin Neonatol ;— Respiratory Disease. Philadelphia: BC Decker, Pediatr Dev Pathol Interactions in Biology and clinical implications.

Masters JRW: Epithelial-mesenchymal interaction during lung develop- human gene diversity and expression patterns based upon 83 million ment. The effect of mesenchymal mass. Dev Biol ;— Nature ;— Cardoso WV: Molecular regulation of lung development. New York: Prentice-Hall, Physiol ;— San Diego, CA: Academic, Science ;— Ann Rev Biochem ;— Lab Invest ;— Molecular and embryolog- Annu Rev Entomol ; actin expression in developing and adult human lung. Differentiation — Homeotic cluster genes, cell Trends Genet ;— Patterning the anteroposterior body axis of Caenorhabditis elegans.

Cold Curr Biol ;— Cardoso WV: Transcription factors and pattern formation in the develop- Development ; Mech Dev ;— Kaplan F: Molecular determinants of fetal lung organogenesis. Mol Genet and keratinocyte growth factor stimulated fetal rat pulmonary epithelial Metab ;— Annu Rev Cell lung. Development ; head DNA-binding-domain family. EMBO J ;— Mol Cel Biol ;— Nat Genet ;— Min H, Danilenko DM, Scully SA, et al: Fgf is required for both limb hepatocyte nuclear factor 3, indicating common factors for organ-specific and lung development and exhibits striking functional similarity to gene expression along the foregut axis.

Mol Cell Biol ;— Drosophila branchless. Genes Dev ;— CCSP promoter. J Biol Chem ;— Mol Cell L—L Biol ;— J Clin Invest ; breathing at birth. Thyroid specific Am J ventral forebrain, and pituitary. Physiol ;L—L Am regions of the foetal brain. J Physiol ;L—L J Histochem Cytochem patterns of growth and differentiation in embryonic lung epithelium. Dyn ;— Child, and Adolescent. An overview. Hilfer SR: Morphogenesis of the lung. Control of embryonic and fetal ;— Vol New York: Marcel Dekker, , pp 99— Lung Biology in Health and Disease, Vol New York: Marcel Dekker, Crouch E, Mecham RP, Davila RM, et al: Collagen and elastic fiber transcription factor family member thyroid transcription factor 1 and car- proteins in lung development.

Mol Cell Biol ; 1st ed. New York: Marcel Dekker, , p Biochim Biophys 1st ed. Acta ;— J Cell Biochem ;— Bingle CD, Gitlin JD: Identification of hepatocyte nuclear factor-3 in endothelial differentiation and blood vessel growth. Proc Natl Acad Sci binding sites in the Clara cell secretory protein gene. Biochem J ; U S A ;— Am J hemorrhage, hemosiderosis, and air space enlargement in neonatal mice. Physiol ;C—C Kauffman SL: Cell proliferation in the mammalian lung. Int Rev Exp growth factor during embryonic angiogenesis and endothelial cell differ- Pathol ;— CHAPTER 1 lial growth factor receptor-1 flt-1 and its ligand suggests a paracrine homeostasis and alveolar macrophage-mediated innate host defense.

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Annu regulation of murine vascular development. Dev Dyn ;— Rev Physiol ;— Perkett EA: Role of growth factors in lung repair and diseases. Curr Opin binding and developmental expression suggest flk-1 as a major regulator of Pediatr ;— Pattern recognition molecules Curr Opin Immunol ;— Cell Biochem J ; Liley H, Bernfield M: Mechanisms of development and repair of the lung.

Am J Respir , pp 11— Cell Mol Biol ;— Effects of cell shape, cell-matrix modulates interaction of Pneumocystis carinii with alveolar macrophages. Am J Med Sci ;— J Appl Physiol attachment of Mycobacterium tuberculosis to alveolar macrophages during ;— Clin Perinatol ;— Binding and neutralization. Monaldi Arch Chest Dis ;— Wright JR: Immunomodulatory functions of surfactant. Semin Respir Am J Physiol Are modeling and remodeling the Chapman HA: Disorders of lung matrix remodeling.

Warburton D, Bellusci S: The molecular genetics of lung morphogenesis the lung.


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Microbes Infect ;— Paediatr Respir Rev ;5 Suppl A — In: defense. Scarpelli EM, ed: Pulmonary Physiology. Fetus, Newborn, Child, and J Clin Invest ; Chest ;— Bevins CL: Antimicrobial peptides as agents of mucosal immunity. Ciba Kelley J: Cytokines of the Lung. Found Symp ;— Ganz T: Biosynthesis of defensins and other microbial peptides. Ciba molecules in pulmonary inflammation and injury. Advan Immunol ; Found Symp ;— Standiford TJ: Cytokines and pulmonary host defenses. Curr Opin Pulm A family of antimicrobial and Med ;— Toxicology ;— Key players or host defense.

Immunol Rev ;— J Allergy Clin J Clin Invest ;— Am J Respir Med ;— The role of cytokines. Curr Opin Infect Dis ;— Ann Rev Relationships to lung inflammation. Ann Sheperd VL: Cytokine receptors of the lung. Pediatr Res ;A. Dranoff G, Crawford AD, Sadelain M, et al: Involvement of granulocyte- tion factor-1 gene in an infant with neonatal thyroid dysfunction and macrophage colony stimulating factor in pulmonary homeostasis. Science respiratory failure. N Engl J Med ;— Lieschke GJ, Stanley E, Grail D, et al: Mice lacking both macrophage- Review, 17 cases, and follow up on the currently year-old boy and granulocyte-macrophage colony-stimulating factor have macrophages first reported by Maroteaux et al in Am J Med Genet ; and coexistent osteoporosis and severe lung disease.

Blood ;— Proc Natl Nature ;— Acad Sci U S A ;— J Med Genet ;— N Engl growth-factor receptor 2 reveals a wide spectrum of mutations in patients J Med ;— Am J Hum Genet ;— Nogee LM: Abnormal expression of surfactant protein C and lung disease. Nogee LM: Genetic mechanisms of surfactant deficiency. Biol Neonate newborns with fatal surfactant deficiency. N Engl J Med ; ;— Jobe, MD. Pulmonary surfactant is a complex substance with multiple is a water-soluble collectin coded on human chromosome The traditional functions of surfactant are the biophys- region to yield a reduced protein of about 36 kd.

SP-A forms ical activities to keep the lungs open, to decrease the work of a collagen-like triple helix that then aggregates to form a multi- breathing, and to prevent alveolar flooding. More recently, most meric protein with a molecular size of kd. SP-A contributes of the components of surfactant were found to contribute to to the biophysical properties of surfactant primarily by decreas- innate host defenses and injury responses in the lung.

Surfactant ing protein-mediated inhibition of surfactant function. The deficiency states occur with prematurity and with severe lung major functions of SP-A are an innate host defense protein injury syndromes. Recent studies in humans and in mice are and as a regulator of inflammation in the lung. SP-A is not a component of surfactants range from lethal respiratory failure at birth to chronic interstitial used for treatment of respiratory distress syndrome RDS.

Our goal is to summarize those aspects SP-B is a small hydrophobic protein that contributes about of surfactant biology that are relevant to children. The phospholipids in surfactant extremely hydrophobic 4-kd protein that is associated with are unique relative to the lipid composition of lung tissue or lipids in lamellar bodies. Surfactant from the imma- mize rapid adsorption and spreading of phospholipids on a ture fetus contains relatively large amounts of phosphatidyl- surface and to facilitate the development of low surface tensions inositol, which then decreases as phosphatidylglycerol appears on surface area compression.

Surfactants prepared by organic with lung maturity. Such surfactants are similar to natural their functions in part elucidated. Composition of surfactant. Saturated phosphatidylcholines a complex sequence of biochemical events that results in the are the major components of alveolar surfactant. The proteins contribute about release by exocytosis of lamellar bodies to the alveolus.

The airspaces back into lamellar bodies for resecretion. The few measurements in large juve- lamellar bodies remain obscure. Ultrastructural abnormalities of nile or adult animals indicate that surfactant is dynamically type II cells with SP-B deficiency and ABCA3 deficiency in full- metabolized by efficient recycling from secretion to uptake for term infants indicate that these gene products are essential for resecretion. The surfactant proteins also are recycled to variable lamellar body formation.

Surfactant secre- infants. In general, alveolar pool sizes are larger per kilogram tion also is stimulated by mechanical stretch such as with lung body weight, secretion rates may be lower, and turnover times distention and hyperventilation. Recycling is very efficient in the newborn. The lamellar bodies unravel to and this large pool decreases to adult values by 1 week of age in form the elegant structure called tubular myelin.

This lipoprotein rabbits, for example. The alveolar surfactant pool size in the array has SP-A at the corners of the lattice and requires at least adult and presumably young child is small relative to other SP-A, SP-B, and the phospholipids for its unique structure. Infants with RDS have alveolar the surface film within the alveolus and small airways. The surface-active tubular myelin forms idly from precursors and then packaged in lamellar bodies for contain SP-A, SP-B, and SP-C while the biophysically inactive storage and secretion.

The time from synthesis to peak alveolar small vesicular forms that are recycled and catabolized contain secretion of the newly synthesized surfactant is about 6 hours in very little protein. The total surfactant pool size is less than adult rabbits. Alveolar life cycle of surfac- Air tant. Surfactant is secreted from lamellar bodies in type II cells. In the alveolar fluid lining layer, the surfactant transforms into tubular myelin and other surfactant protein—rich forms that facilitate surface adsorption.

Reuptake Degradation. Lysosome Lamellar body Macrophage Multi-vesicular body Lysosome. Type II cell Type I cell. Pulmonary edema and products of lung injury The static effects of surfactant on a surfactant-deficient lung can accelerate form conversion and cause a depletion of the are evident from the pressure-volume curve of the preterm lung surface active fraction of surfactant despite normal or high total Fig. Preterm surfactant-deficient rabbit lungs do not begin surfactant pool sizes. Granulocyte-macrophage colony-stimulating and surface tension of the meniscus of fluid in the airspace factor deficiency prevents alveolar macrophages from cataboliz- leading to the lung unit.

The important concept is that the alveolar pool expansion, the radius increases and the forces needed to finish of functional surfactant is maintained by dynamic metabolic opening the unit decrease. Surfactant decreases the opening processes that include secretion, reuptake, and resecretion pressure from greater than 20 to 15 cm H2O in this example balanced by catabolism. Because surfactant does not alter airway diameter, the decreased opening pressure results from surface adsorption of the surfactant to the fluid in the airways.

A particularly important effect of surfactant on the surfactant- Alveoli are polygonal with flat surfaces and curvatures where the deficient lung is the increase in maximal volume at maximal walls of adjacent alveoli intersect. Alveoli are interdependent in pressure. In this example, maximal volume at 30 cm H2O is that their structure is determined by the shape and elasticity of increased over two times with surfactant treatment. Surfactant neighboring alveolar walls. The forces acting on the pulmonary also stabilizes the lung on deflation. Although the surface tension of surfactant decreases deflation.

This retained volume is similar to the total volume of with surface area compression and increases with surface area the surfactant-deficient lung at 30 cm H2O and demonstrates expansion, the surface area of an alveolus changes little with how surfactant treatments increase the functional residual tidal breathing. The low surface tensions resulting from sur- capacity of the lung.

When positive pressure and is chemotactic for alveolar macrophages and peritoneal is applied to a surfactant-deficient lung, the more normal macrophages. SP-A also inflated lung. Effect of surfactant treatment on surfactant deficient lungs. These idealized pressure-volume curves illustrate the effect of surfactant treatment with natural sheep surfactant on the opening pressure, the maximal lung volume, and the deflation stability of lungs from preterm rabbits. J Appl Physiol ;— Thus, SP-A may have a com- whelming inflammatory reaction within the pulmonary plex role in adaptive immune responses.

Although SP-B can inhibit bilateral infiltrates on chest x-ray, and a pulmonary capillary bacterial growth in vitro, overexpression of SP-B or reduced wedge pressure of less than 18 mm Hg or absence of clinical expression of SP-B in the lungs of mice did not alter bacterial evidence for left-sided heart failure. The etiology of ARDS clearance, suggesting that the SP-B is not involved in innate host is multifactorial and can occur in association with lung injury defense. Impairment of surfactant with ARDS can result from inhibi- SP-D increases phagocytosis of gram-negative and gram-positive tion, degradation, or decreased production.

Plasma dependent uptake of Escherichia coli, Streptococcus pneumoniae, proteins known to inhibit surfactant function include serum and Staphylococcus aureus by neutrophils. In addition to binding albumin, globulin, fibrinogen, and C-reactive protein. The composition of surfactant is altered in ARDS. Early maturation is thought to occur in response to acids, and proteins likely represent alveolar type II cell injury with fetal stress resulting in increased fetal cortisol levels, or by expo- altered metabolism, secretion, or recycling of components.

SP-A sure of the fetal lung to inflammation as a result of chorioam- and SP-B concentrations are also reduced in the lungs of nionitis. Maternal treatments with corticosteroids to decrease patients at risk for ARDS, even before the onset of lung injury the risk of RDS are routinely given if preterm delivery before clinically. Although this amount is similar SP-A-deficient mice have normal survival without changes in in amount to the surfactant recovered from healthy adult surfactant composition, function, secretion, and reuptake; humans, surfactant from the preterm infant has decreased func- however, there is no tubular myelin.

However, polymorphisms in the human genes for overdistention of the delicate preterm lung can be avoided. They then are treated with surfactant. Preterm infants will tuberculosis. SP-B deficiency demonstrate the critical role of SP-B in surfac- Full-term infants with severe meconium aspiration or pneu- tant function, homeostasis, and lung function.

Current practice is to treat most any infant with multivesicular bodies but did not have lamellar bodies, and the severe respiratory failure with surfactant because there seems to proteolytic processing of pro-SP-C the preprocessed form of be no contraindications. SP-C was disrupted. While there are differ- have been associated with chronic lung disease in infants.

Mice ences in composition, the clinical results do not demonstrate and infants without the adenosine triphosphate—binding cassette any compelling differences in clinical responses. Surfactants that contain synthetic peptides or SP-C-deficient mice survive and have normal surfactant surfactant proteins are being developed for clinical use. Surfactant content and composition stitium, infiltration with inflammatory cells and macrophages, are altered in ARDS, resulting in decreased surface activity, fibrosis, and abnormalities of the respiratory epithelium.

ARDS results in primarily surfactant ulation of surfactant homeostasis. SP-D also regulates alveolar inactivation rather than deficiency, and surfactant inhibitors macrophage function because SP-D-deficient mice accumulate such as plasma proteins and inflammatory mediators decrease foamy activated macrophages in the lung and develop emphy- the efficacy of treatment. Several recent pilot studies in adults sema due to increased oxidant and metalloproteinase expression and children have examined surfactant therapy in ARDS.

The lower- approaches to mechanical ventilation. The original randomized dose group had significant improvement in oxygenation index, trials of surfactant for RDS evaluated treatments given after the and patients were weaned more rapidly from the ventilator com- disease was established, generally after 6 hours of age. Other pared with the standard therapy group. Results in the high-dose trials evaluated treatment of all high-risk infants soon after birth group were not different from those of the standard therapy group.

Subsequent trials demonstrated that treatments In a large trial, full-term infants with severe respiratory fail- of the highest-risk infants generally infants with birth weights ure treated with surfactant had improved oxygenation and less than 1 kg as soon after birth as convenient and before required less extracorporeal membrane oxygenation ECMO significant mechanical ventilation will minimize lung injury. No large or definitive trials of surfactant for res- pressure CPAP , and the decision to treat with surfactant can piratory failure in children have been performed.

Representative be made after the initial stabilization at birth. An advantage responses have improved oxygenation and decreased ventilator of allowing the infant to breathe spontaneously with CPAP days,35 results that are consistent with the larger trials in adults used to recruit and maintain FRC is that hyperventilation and with ARDS. There is strong experimental evidence that alterations in the Infect Immun treatments can improve oxygenation, improve lung compliance, ;— The Cochrane Library, Issue 2.

Oxford, UK: Update Software, J Appl Physiol ; — Nogee LM: Genetics of the hydrophobic surfactant proteins. Biochim proteins in lung and serum before and after onset of ARDS. Am J Respir Biophys Acta ;— Crit Care Med ;— Am J Physiol ; 5. Biochim Biophys Acta ;— J Infect Dis ;— N Engl J Med ; — In: Robertson From molec- SP-B deficiency.

Amsterdam: Elsevier, A novel method with stable isotopes. Captive bubble surfactometry. Biochim Biophys Acta ; cellular nonspecific interstitial pneumonitis in one kindred. Am J Respir — Am J Respir Crit Care Am J Respir Crit J Appl Physiol ; Am J Respir LeVine AM, Whitsett JA: Pulmonary collectins and innate host defense of tant beractant use in the treatment of term infants with severe the lung. Survanta in Term Infants Study Group. J Pediatr ; Pathobiology ; A randomized Intens Care Med ;— Crit Pediatr Res ;— Care Clin ;— Wohl, MD.

During the embryonal period of lung costeroids and the postnatal administration of surfactants. Further However, respiratory distress of the newborn still ranks fifth as a branching of the airways, which is more or less dichotomous, contributor to infant mortality. After infancy, mortality rates occurs during the pseudoglandular period, so named because related to respiratory causes are low but are still included in the of the appearance of the lung on microscopic section.

By the 10 most frequent causes of death.

Respiratory morbidity rates, 17th week of gestation, the full number of generations of on the other hand, are high, and respiratory diseases continue to conducting airways has been established. During fetal life, the thick, Certain respiratory pathogens are age specific: they produce columnar, glycogen-rich epithelium develops cilia and thins, disease of consequence at certain ages and not at other ages. The thinning of the Some respiratory infections, such as cytomegalovirus pneumonia, epithelium continues postnatally in the human.

Although the depend on exposure in utero. Other infectious agents, thins to a columnar type in the bronchioles, there are substan- such as chlamydia and group B streptococci, cause pneumonia tial differences. Acute epiglottitis, rarely seen since Hemophilus The rate of tracheal mucociliary clearance, studied in animals, is influenzae B vaccination became commonplace, is usually, but greater in the young adult than in the infant.

Mycoplasma is present in the airways of the fetus early in development and rarely produces disease in preschool children but is a common extends from the trachea to the alveolar ducts in both newborns cause of bronchopneumonia in school-aged children and young and adults. In the rabbit, the amount of to development of the immune system, of defenses within the smooth muscle is increased and the amount of cartilage is lung itself,2,3 and to age-related exposure.

The influence of age decreased in the immature compared with the mature animal. Some of the steps in the development of the lung a limited number of anatomic studies in humans, and the data have a strong influence on lung function during childhood and are conflicting. The limited anatomic of reviews of lung development in recent years elucidating the and more extensive physiologic studies on excised human lung mechanisms underlying morphogenesis, molecular regulation, performed by Hogg and co-workers17 suggest that peripheral maturation, and vascular development.

Comparison of peripheral and central airway conduc- N Engl J Med ; In all likelihood, considerable life and early childhood by forming new structures i. Only later do they grow by enlargement9 units may go undetected by the pediatrician but may influence Fig. Dunhill18 carried out morphome- formation of saccules at the end of the budding airway. These tric studies on lungs obtained at autopsy. His data suggest that structures—larger, thicker walled, and more irregular than most of the million alveoli present in the adult lung are alveoli—are probably capable of sustaining gas exchange.

From formed by the age of 2 years. Current data suggest that this is an 28 to 32 weeks of gestation, some of the subdivisions of the underestimation of the number or alveoli present in the adult saccules have the cupped shape and single capillary layer charac- lung19 and that mean data have a wide range. The variability in teristic of alveoli, but infants born at less than 28 weeks have the number of alveoli present at a given age20 makes the age at virtually no alveoli.

Approximately million alveoli are present at birth in the Nonetheless, a substantial fraction of the total number of alve- full-term infant. The number is likely to be extremely variable. Thereafter, Pulmonary hypoplasia is diagnosed when a baby has an associated growth of alveoli takes place for the most part by enlargement. Diagram showing that the lung grows initially by increasing the number of alveoli by the ingrowth of septa and formation of the alveolar ducts.

Thorax ; It seems reasonable to assume that factors that influence pores of Kohn and epithelium-lined channels between terminal. These first year of life would be of particular importance to lung structures may be present in the infant lung, but they are prob- development. Some of these factors are under active investiga- ably not of sufficient size to allow for air drift. Although collateral tion. Nutrition,21 vitamin A,22 administration of corticosteroids,23 pathways in the adult are probably not of great significance for hyperoxia,24 and maternal smoking25 play important roles in ventilation, they do help to prevent absorption of gas in regions lung development.

Although both collagen and elastin are distal to airway obstruction.

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The relative absence of functional important in airway morphogenesis and branching, the intersti- collateral pathways probably contributes to the patchy atelectasis tium of the lung contains little collagen and elastin during late so common in airway disease of infants and young children. Elastin, which appears to be closely related to the development of alveoli, increases during early postnatal life.

Considerable structural changes occur in the chest wall, partic- Lung collagen also increases during postnatal life. The forma- ularly during early postnatal life. In infancy the ribs are oriented tion and changing ratio of elastin and collagen probably con- in a horizontal plane. As growth occurs, they slant in a progres- tribute to the change in volume-pressure relationships of the sively caudal direction. By 10 years of age they have the down- lung and to the increased stiffness of the lung with increasing ward slope of adults.

Calcification of costal cartilage can continue into old age. The pulmonary arterial system develops by vasculogenesis, the In adults, lung volume at end-expiration or functional resid- production of vessels from endothelial cells differentiating ual capacity FRC is mainly set passively by the balance from mesenchymal precursors, and angiogenesis, the sprouting between the inward recoil of the lung and outward recoil of the of new vessels from preexisting vessels.

It appears that until about chest wall. Newborns have compliant chest walls that would 17 weeks of gestation new vessels are produced by vasculogenesis allow nearly complete collapse of lungs if it were not for the and the airway acts as a template. Postnatally there is a marked activity of muscles. Expiratory braking occurs by active glottic increase in the number of arteries in the acinus that seem to be narrowing and by the interruption of expiration by the onset of formed by angiogenesis.

Indeed, the major function ment of acinar arteries and capillaries parallels the postnatal devel- of the active Hering-Breuer reflex in infants may be to terminate opment of alveoli. The pulmonary veins originate as proliferating expirations before lung volume gets too small.

This response endothelial cells that migrate away from the artery, are surrounded may disappear once the chest wall has become stiff enough by lymphatic channels, and never develop any smooth muscle. End-expiratory lung volume is actively The origins of smooth muscle cells include cells that migrate maintained by infants until about 6 to 12 months of age, when from the airway into the vessel wall at the penultimate genera- the passive characteristics of the lung and chest wall appear to tion of the airway and form the innermost layer of the vessel determine resting end-expiratory lung volume.

Later, fibroblasts differentiate and express both alpha and The easy collapsibility of the rib cage is probably advanta- gamma actin. Finally, endothelial cells, later in development, geous during birth, when it allows for deformation of the chest express alpha actin and form smooth muscle cells. Thereafter the the fetus and young child, and during childhood, muscle collapsibility is probably disadvantageous but affordable in a extends out to the alveolar duct, and in the adult out to the healthy infant because of relatively small metabolic demands.

A number of studies of the pulmonary vascular system The parenchyma of the lungs develops during the postnatal relating structure to function have been carried out, and these period, and the rib cage may be thought of as doing the same.

Pediatric Pulmonology: A Developmental History in North America | Pediatric Research

What vascular, and alveolar development. But the relationships are not infants and adults. This is an active area of investigation and as direct as they might seem. In the adult, collateral ventilation—the movement of gas from Changes in the shape, magnitude, or curvilinearity of volume- one acinus to another—occurs through holes in the alveoli the pressure curves do point to maturational changes in growing lungs. The lung volume at which airways close is higher in younger in normal subjects or changes associated with diseased lungs. Lung recoil is reduced greater than the reduction in resistance during the first years in younger lungs29—31 and increases as the lungs mature in early of life.

It is another measure of greater in infants younger than 1 year compared to children airway properties, depending on the physical properties of the older than 1 year. Furthermore, the relationship between chest gas, the physical properties of the airway wall, the elastic recoil wall and lung compliance changes. In infants chest wall compli- of the lung, the degree of lung inflation, and the resistive pres- ance is threefold greater than lung compliance, but in children sure losses along the airway.

Nevertheless, MEF-volume curves and adults these values are virtually equal. These marked physi- can be interpreted in terms of the relative size of airways and ologic changes in mechanical properties of both the lung and parenchyma. The average slope of a flow-volume curve i.

This rate mimic those of the lung in young children in that they are more depends on the relative sizes of the airways and lung parenchyma. However, for individuals 2 to airway of a given size and resistance. Similarly, the greater the 16 months of age, curves are very similar, probably reflecting size of the airways, and hence the lower their resistance, the increasing inward recoil of the lung balanced by increasing more rapidly a lung of a given size empties. Estimates of rates of outward recoil of the chest wall.

Overall, the total respiratory lung emptying can be made for infants, children, and adults. This upper airway resistance airway growth throughout childhood. Compliance in. Deflation volume-pressure curves of the lung. A, Data plotted from curves on excised lungs obtained by Fagan. B, Data taken from the work of Zapletal and co-workers31 are plotted in solid lines.

Age is estimated from height. For comparison, the curve for subjects older than 45 years is shown with dashed lines. The curve from elderly subjects dashed line resembles that from a 7-year-old. CHAPTER 3 shape of the volume-pressure curve suggest that to some extent and the increased response to bronchoconstricting agents. As the volume of It does not require a greater inflammatory response, cytokine the lung parenchyma enlarges relative to airway volume, specific release, or smooth muscle response, although these may or may conductance and indices of rates of emptying fall.

However, not be present. Some individuals apparently have relatively large airways and small lungs, and vice versa. Some between airway and lung parenchyma growth begins in early life of these differences, such as the reduced lung recoil, are shared and presumably is genetically determined. Whether it bears on by the elderly and likely influence the pattern of respiratory disease susceptibility remains to be seen, but there is increasing disease in that population as well.

The young lung lacks elastic recoil; as a result, airways are to physiologic indicators of lung and airway size established less well supported. This will be particularly true if there during early infancy. Airway walls of young lungs may be thicker. The chest wall is relatively more compliant in the young determine the contractile response of smooth muscle. However, child and stiffens with increasing age.

As a result, the airway reactivity may be modulated by cyclic changes in tidal infant can develop paradoxical respiration. Respiratory volume and cyclic changes in force applied to the smooth mus- muscle activation during inspiration can produce inward cle. The appar- within the airway. The deformability of the chest wall influences findings on Edema of the outer airway wall, which occurs in viral illnesses, physical examination.

Chest wall—abdominal paradox pulmonary overcirculation, and inflammation of the airway may be normal in the premature infant during REM wall, uncouples the attachments of the parenchyma to the air- sleep but not in the older child or adult. This results in increased airway reactivity to inhaled 4. Finally, infants and children have frequent respiratory bronchoconstrictors. It may be that the profuse of a bronchoconstrictor, methacholine or histamine, are nebu- secretions are aspirated and with a shorter path length to lized and inhaled.

The dose required to produce a decrease in a peripheral airways, the epithelium lining these structures measured parameter of some fixed percentage of baseline value becomes infected. Normal children 6 months to 1 year of age have of parenchymal—airway wall attachments. The effects of inspiratory flow rates that approximate nebulizer output and any degree of airway smooth muscle contraction will be will deliver a higher dose of the bronchoconstricting agent to exaggerated and contribute to the uneven ventilation and the airways.

Preliminary data for Natl Vital Stat Rep ; Whitsett JA: Intrinsic and innate defenses in the lung. Intersection of path- The younger lung thus has many of the features of the ways regulating lung morphogenesis, host defense, and repair. J Clin Invest asthmatic lung. These structural features may be important ; J Clin Invest ; Control of embryonic and fetal Ann Rev Physiol ; J Appl Physiol ; 5. Physiol ; J Appl Physiol 6. McMurtry IF: Introduction. Pre- and postnatal lung development, matura- ; Fagan DG: Post-mortem studies of the semistatic volume-pressure 7.

Hislop AA: Airway and blood vessel interaction during lung development. J Anat ; Bucher U, Reid L: Development of the intrasegmental bronchial tree. The pattern of branching and development of cartilage at various stages of J Appl Physiol ; Hislop A, Reid L: Development of the acinus in the human lung. Thorax Am Rev Respir Dis ; J Appl Physiol James A, Christmas T: Mechanisms of bronchial hyperresponsiveness in ; Am Rev Respir Dis ;A Care Med ; Differentiation ; infants and children.

J Appl Lung Physiol ; Growth and Development. Stocks J, Godfrey S: Specific airway conductance in relation to postconcep- In: Fishman AP, III, Part 1. Mechanics of Breathing. The Respiratory System. Bethesda, Md: American Physiological Society, Dunhill MS: Postnatal growth of the lung. N Engl J Med In: ; Fishman AP, ed: Handbook of Physiology.

Vol III. Bethesda, Md: American Physiological for recurrent wheezing respiratory illnesses during the first three years of life. Society, , p Semin Perinatol ; Fredberg JJ: Frozen objects. Small airways, big breaths, and asthma. Clinical implications. J Allergy Clin Immunol ; A morphologic and The saga of a frustrated cell. Pediatr Res ; Am Rev Semin Neonatol ; Lancet ; Am Rev Respir Dis ; West, MD. Knowledge of the normal development and physiologic func- within the cell with a basal body that is oriented in the direction tion of the lungs is required to understand the pathophysiology of mucous movement.

The shaft of the cilium has a central pair that is seen in disease. Historically, our understanding of lung of single tubules that are connected via radial spokes to nine function was derived solely from clinical observation and post- peripheral pairs of tubules. The tip of the cilium has tiny hook- mortem histologic examination. The development of invasive lets that probably help grab the gel component of the mucous and noninvasive techniques that were capable of assessing lung layer and propel it forward.

Primary ciliary which are covered in detail in other chapters in this section. This dyskinesia PCD is a group of disorders that includes chapter will concentrate on organ physiology.

Mucous glands, which are present in large and small bronchi, Because detailed descriptions of lung anatomy are available are the chief source of airway secretions, and contain both elsewhere, this section will focus on selected aspects of gross serous and mucus-producing cells. Goblet cells are seen in the and microscopic anatomy to enable the reader to understand trachea and bronchi. They produce mucin within their rough the physiologic changes that occur in congenital and acquired endoplasmic reticulum and Golgi apparatus.

Mucin is a viscous lung disease. There are The basic structure of the airways is already present at birth, and several other cell types found within the airways; however, their thus neonates and adults share a common bronchopulmonary functional significance is less well understood. The basis cell, anatomy Fig. When airways divide, they do so by dichoto- commonly seen within the pseudostratified columnar epithe- mous branching, but the number of times that branching occurs lium, is undifferentiated and may be a precursor of ciliated or varies.

For example, there may be anywhere from 10 hilar region secretory cells. The brush cell has a dense tuft of broad, short to 25 basal region airway divisions before the gas-exchanging microvilli and is only rarely seen within the conducting airways units are reached. This airway variability has physiologic impli- and alveolar space. Clara cells are seen exclusively within the cations; different pathways will have different resistances to air- bronchiolar region of the lung.

Their physiologic role has been flow, and a heterogeneous distribution of gases or inhaled uncertain, but data suggest that they may play two important particles may occur. As the bronchi branch and decrease in size, roles. First, because they contain but do not synthesize sur- they lose their cartilage and become bronchioles. Ultimately, factant apoproteins, they may recycle surfactant within the a terminal bronchiole opens up into the gas-exchanging area of distal lung unit.

Second, they are capable of actively transport- the lung Fig. Ciliated cells predominate throughout this believed to possess neuroendocrine properties. They are known epithelium and are responsible for propelling mucus from the under a variety of names, including Feyrter or Kulchitsky cells. This mucociliary transport Histochemical staining indicates that they contain a variety of system is an important defense mechanism of the lungs.

The vasoactive peptides, including serotonin and kinins, so these cells mucous layer has two parts, a superficial gel layer and a deeper may belong to the class of amine precursor uptake and decar- sol layer. The cilia form a dense, long carpet on top of the boxylation APUD cells. These neuroendocrine cells are epithelial cells, and their coordinated to-and-fro action innervated and are found more frequently, and in groups propels the gel mucous layer toward the oropharynx. Cilia are neuroepithelial bodies , within the fetal airways or in pediatric a derivative of the centrioles, and there are approximately of disorders characterized by chronic hypoxemia e.

The cilia are anchored monary dysplasia. Cartilage adds structural rigidity to the airway and thus plays an important role in maintaining air- way patency, especially during expiration. Congenital deficiency of airway cartilage and hence airway instability has been associ- ated with bronchiectasis Williams-Campbell syndrome and congenital lobar emphysema. The smooth muscle content of the airway also varies with its anatomic location.

In the largest airways a muscle bundle con- nects the two ends of the C-shaped cartilage. As the amount of cartilage decreases, the smooth muscle assumes a helical orienta- tion and gradually becomes thinner, ultimately reaching the alveolar ducts. Muscle contraction increases airway rigidity in all airways and terminal respiratory units.

Although it has been widely assumed that the airway muscles of newborn infants are inadequate for bronchoconstriction, this assumption is not correct. Indeed, pulmonary function test results have demonstrated that airway resistance can be altered with bronchodilating drugs. The nomenclature of bronchopulmonary anatomy, from a genital heart disease, in which hypertrophy of the airway report by the Thoracic Society in A, Right lateral view. B, Anterior view. In the main stem structures distal to the terminal bronchiole: the respiratory bronchi, cartilage is present in C-shaped rings. However, as bronchioles bronchioles with alveoli budding from their walls , further branching occurs, progressively less cartilage is present, alveolar ducts, and alveoli.

This unit is also known as an acinus. The architecture of the lung. A, Fresh frozen cat lung. Segmental cartilaginous bronchus and branches. Terminal bronchiole with many alveolar ducts arising from it.