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464 S E C T I O N V   Pediatric Critical Care: Pulmonary • Fig 41.2  ​Internal structure of a cilium (no cell membrane evident) in which two axial tubules and nine peripheral duplex tubules are seen Dynein arms are attached to several of the peripheral duplex tubules (313,500) the deeper layer This difference in consistency of the mucous layer allows the cilia to function properly, allowing a power and recovery stroke mechanism The secretions include lysozyme, antileukoprotease, lactoferrin, and immunoglobulin A (IgA) The secretory component of IgA is synthesized in bronchial gland cells and expressed on their basolateral cell surfaces, to which IgA dimers synthesized by plasma cells bind The complex is endocytosed by the glandular cell and then is secreted from its luminal surface Neuroendocrine cells can be solitary near the basal lamina between columnar cells or in collections called neuroepithelial bodies that occur near branch points of bronchi.15 The neuroendocrine cells are more abundant in the fetus and likely have a role in lung growth or maturation Although originally defined as having a lumen diameter of less than mm, the term small airway usually refers to a bronchiole Histologically, the bronchiole is characterized by a transition from pseudostratified tall columnar epithelium to a more cuboidal ciliated form In addition, the mucous goblet cell is replaced by the nonciliated club cell, formerly known as the Clara cell (Figs 41.3 and 41.4) In the bronchiolar epithelium, a ratio of about three ciliated cells to two nonciliated cells lines the lower airways The club cell is identified as a dome- or tongue-shaped cell that protrudes into the bronchiolar lumen among the shorter ciliated cells The club cell has varying features according to species but possesses an abundance of agranular reticulum and secretory granules Club cells synthesize and secrete club cell secretory protein (CC10, CC16), a unique 10kDa protein similar to rabbit uteroglobin that has antiinflammatory and immunoregulatory functions.16 In addition, club cells secrete surfactant-associated proteins A, B, and D Importantly, the club cell also functions as a progenitor cell that differentiates into ciliated cells following injury Some investigators have shown that the club cell can differentiate into a type II epithelial cell.17 Within the wall of the bronchiole, the muscular layer becomes more prominent, and submucosal glands and cartilage are absent The bronchiole segment ends as a terminal bronchiole, which marks the terminus of the conducting portion of the airway The terminal bronchiole branches into two generations of respiratory bronchioles that, through further divisions, give rise to additional respiratory bronchioles with more alveoli in their walls—so-called second- and third-order respiratory bronchioles By definition, • Fig 41.3  ​Distal conducting airway mucosa composed of some ciliated epithelial cells showing a terminal bar (arrows) and a nonciliated club cell (arrowheads) (Hematoxylin-eosin stain, 3400.) respiratory bronchioles are alveolated, and they branch into two to three generations of alveolar ducts The alveolar ducts are defined as those channels from which a series of alveoli open and are histologically characterized by having small club-like ends that contain muscle sphincters and elastic fibers The ducts open into a final generation of alveolus-lined spaces, the multiloculated cupshaped alveolar sacs (Fig 41.5) Definitions of Special Lung Unit and Alveolar Formation Each bronchopulmonary segment is further compartmentalized into smaller units termed pulmonary lobules Each pulmonary lobule is supplied by a bronchiole that divides into a cluster of three to five terminal bronchioles and their associated respiratory tissue situated at the end of a bronchial pathway The pulmonary lobule is roughly to cm in diameter and pyramidal in shape It is bound by delicate connective tissue septa in which small proximal branches of pulmonary veins travel The portion of the pulmonary lobule distal to the terminal bronchioles and consisting of several respiratory bronchioles, alveolar ducts, and, ultimately, alveoli is termed the pulmonary acinus The acinus, which is approximately spherical in shape and has a diameter of about mm and a length of to 10 mm, is the gas-exchange portion of the lung At the alveolar level, many changes occur in the postnatal period Although there is disparity concerning the time in which alveolarization is completed, evidence links the postnatal development of alveoli with elastic tissue fiber deposition.18 At birth, primitive alveoli called saccules are evident, but approximately 50 million alveoli are already formed.19 The number of alveoli in a normal adult can vary from 300 to 500 million, and they have a diameter of 150 to 200 mm The early work by Dunnell20 suggesting that new alveolar formation ceased at about age years has been challenged by Thurlbeck,21 who has shown that alveolarization appears to be nearly complete at about age years Lung volume correlates with body size, but alveolar surface area correlates with metabolic activity; thus, alveoli become more complex in shape during maturation and as increasing oxygen is required 465 Alveoli Respiratory bronchioles Terminal bronchioles Bronchi Trachea CHAPTER 41  Structure and Development of the Lower Respiratory System • Fig 41.4  ​Respiratory tract epithelia There is a progression from pseudostratified columnar epithelium with ciliated, goblet, and basal cells in the large conducting airways (top circle) to a more cuboidal ciliated epithelium in the small conducting airways with nonciliated club cells (middle circle) In the alveolar epithelium, flattened type I pneumocytes and cuboidal type II pneumocytes are present and are associated with an extensive capillary network (box) (Courtesy Satyan Lakshminrusimha.) Alveolar-Capillary Unit AD RB TB • Fig 41.5  ​Distal conducting airway with transition to respiratory airway AD, alveolar duct; RB, respiratory bronchiole; TB, terminal bronchiole Individual alveoli are indicated by arrows (Hematoxylin-eosin stain, 340.) The alveolar-capillary unit is highly specialized to maximize diffusion between the blood and air gases (Fig 41.6) The alveolarcapillary unit is composed of three major constituents: (1) the epithelial lining of the alveolus; (2) capillary endothelial cells; and (3) a mixture of cellular and extracellular interstitial components.22 This alveolar-capillary bed is the most extensive in the body and is contained within the epithelium-lined walls of adjacent alveoli, forming a gridlike network The internal surface area of the adult lung is 70 to 80 m2, of which 90% covers the pulmonary capillaries; thus, the air-blood surface available for gas exchange is 60 to 70 m2.22 The endothelial cells, which constitute about 30% of the total lung cells, contain few intracellular organelles that are clustered together within the cytoplasm, allowing the cell to maximize its surface area A number of adenine nucleotides, vasoactive amines, prostaglandins, vasoactive peptides, and lipoproteins can be metabolized and taken up within the numerous pinocytotic vesicles characteristic of pulmonary endothelial cells In addition to gas exchange, endothelial cells synthesize and secrete various locally acting substances such as nitric oxide, endothelins, 466 S E C T I O N V   Pediatric Critical Care: Pulmonary AS C I C ATI AS E AS • Fig 41.6  ​Both surfaces of the alveolar wall that separates the alveolar spaces (AS) are covered by thin extensions of alveolar type I (ATI) epithelial cells The capillary (C) is lined by endothelium (E) The epithelium and endothelium rest on a fused basement membrane on the thin portion of the alveolar wall and are separated by an interstitial space (I) in the thick portion of the alveolar wall (35500) prostacyclin, tissue plasminogen activator, and thrombomodulin Other functions include liquid and solid exchange and enzyme activity within the walls of the caveolae At the ultrastructural level, the blood-air barrier consists of a 0.1- to 0.2-mm thick septum composed of a capillary endothelial cell and the type I pneumocyte with their intervening fused basal laminae Within thicker portions of the alveolar wall, the alveolar epithelium and capillary endothelium are separated by the interstitial space The connective tissue space, or interstitium of the lung at the alveolar level, does not have lymphatics, but it can accumulate fluid that can be absorbed into the lymphatic system, which usually ends at the respiratory bronchiolar level The interstitial cell population includes resident and migratory cell populations Normally, the interstitium contains macrophages, pericytes, myofibroblasts, mast cells, infrequent lymphocytes, and a few cells that are best termed undifferentiated, mesenchymal, or pluripotent because in disease they can differentiate into various cell types, including fibroblasts, smooth muscle cells, and others Greater than 25% of the interstitial cells cannot be identified definitively with the electron microscope; thus, it is understandable why most of the cells cannot be identified by light microscopy without special cell marker stains Two epithelial cell types line the alveoli Type I cells have thin cytoplasmic extensions and a large surface area covering approximately 90% of the total alveolar surface (Fig 41.7) Numerically, they form only about 40% of the epithelial cells; the type II cell, which is cuboidal, constitutes 60% of the total number of epithelial cells but contributes less than 10% of the total alveolar surface area Type I cells are exquisitely well adapted to allow for the rapid exchange of gases, and their micropinocytotic system likely plays a major role in the transport of solutes, such as albumin and immunoglobulin, in small quantities They can be induced to ingest some particulates and can increase their number of pinocytotic vesicles, but they are not active in surfactant uptake The type II cell is the regenerative cell of the alveolar epithelium, serving as the stem cell following injury It can repopulate the alveolar surface in about days It is cuboidal in shape and numbers only about one per alveolus Ultrastructurally, the type II cell has characteristic surface microvilli and cytoplasmic AS • Fig 41.7  ​Electron micrograph showing the thin side of the air-blood barrier The thin cytoplasmic extension of the type I epithelium contains only a few vesicles and shares a fused basement membrane with the endothelium, which contains many caveolae (318,000) AS, alveolar space; C, capillary multilamellar inclusions, which are the intracellular cytoplasmic storage forms of pulmonary surfactant (Fig 41.8) The inclusions evolve from multivesicular bodies or lysosomal granules, which progressively acquire the characteristic lamellae through fusion and condensation In addition to its roles in the synthesis, secretion, and reuptake of surfactant, the type II cell synthesizes arachidonic acid metabolites; synthesizes and secretes connective tissue components of the basement membrane, including fibronectin; synthesizes and secretes components of the complement system; expresses class II proteins of the major histocompatibility complex among others; and has been found to be a critical source of many different growth factors during injury and repair.23 Considerable data demonstrate clearly that there are several populations of macrophages: intraalveolar, septal (interstitial), pulmonary intravascular, and airway Within the alveolar spaces, alveolar macrophages are abundant and form an important arm of the defense mechanism of the lung (Figs 41.9 and 41.10) They number approximately 23 109 in the lung (10% of the total cells of the alveolar compartment); 50 to 100 are estimated per alveolus They derive from three sources: bone marrow via blood monocyte, the interstitial macrophage pool, and proliferation of macrophages in the alveolar space They are actively phagocytic and scavenge the surface of the alveoli for respired particulates (macrophages as so-called dust cells) Although seen free-floating in alveolar spaces in light microscopic preparations, the alveolar macrophage crawls along the surface of epithelium, adhering with its filopodia The macrophage has remarkable metabolic activities, has known immune functions, and is involved in CHAPTER 41  Structure and Development of the Lower Respiratory System • Fig 41.8  ​Cytoplasm of the alveolar type II cell has abundant lamellar inclusion bodies and surface membrane microvilli (37500) 467 • Fig 41.9  ​Alveolar macrophages recovered from bronchoalveolar lavage fluid contain abundant lysosomes and other cytoplasmic contents, including lipid droplets and surfactant remnants (35300) • Fig 41.10  ​Sections obtained from infants who died with bronchopulmonary dysplasia Pulmonary macrophages present within air spaces were immunostained (brown stain) with anti-CD45, a general leukocyte marker Leukocytes are also identified within the alveolar walls and capillaries (Hematoxylin counterstain: 3200 left, 3400 right.) (Original lung section courtesy Dr Gloria Pryhuber.) lung injury and repair phenomena Alveolar macrophages also play a role in surfactant uptake, removal, or catabolism More than 100 macrophage-synthesized mediators have been identified, including many proinflammatory cytokines, and numerous ligands have been demonstrated In normal bronchoalveolar lavage fluid, 90% of the cells are alveolar macrophages and 1% to 5% are lymphocytes (T-cell lymphocytes constituting 60% to 70% and B cells 5% to 10%) Lung Circulation Pulmonary Vascular System The pulmonary circulation is furnished by the pulmonary and bronchial vascular systems.24,25 During gestation, branches of the pulmonary arterial system are thick-walled and contain a medial 468 S E C T I O N V   Pediatric Critical Care: Pulmonary layer of smooth muscle At birth, the pulmonary artery and aorta are comparable in medial thickness and configuration Elastic fibers tend to be long, uniform, unbranched, and parallel with one another Following birth the pulmonary vasculature undergoes extensive remodeling and by years of age shows a media composed of short, branched, and loosely arranged elastic fibers When fully matured, the pulmonary artery and its thickness are only about 60% that of the aorta Only a few muscular arteries are seen accompanying terminal bronchioles at birth Following birth, when pulmonary arterial pressures fall to normal levels, the muscle fibers diminish Initially, new vessels without muscle are formed, along with new respiratory units during lung growth Smooth muscle extends peripherally into small arteries slowly, reaching arterioles at the respiratory bronchiolar level at months, alveolar duct level at years, and some alveoli at age 10 years.26 The criteria for recognizing various types of pulmonary vessels were put forth by Brenner in 1935.27 The pulmonary arteries, which exceed 1000 mm in external diameter, are called elastic pulmonary arteries and traverse with the cartilaginous airways They extend from the hilum to nearly halfway in the bronchial tree of the newborn, a pattern completed by week 16 of gestation and retained into adulthood Pulmonary arteries measure between 100 and 1000 mm in diameter and have a distinct muscular media and internal and external limiting elastic membranes The muscular arteries of the lung have thinner media than their counterparts in the systemic circulation Muscular pulmonary arteries branch with the bronchial tree and lie close to bronchi and bronchioles (Fig. 41.11) Pulmonary arterioles are vessels that measure 100 mm in diameter and have only an endothelial lining and a single elastic lamina with little if any muscular media These vessels usually are seen at the level of the alveolar ducts and in certain sites within the alveolar walls Pulmonary capillaries are nonfenestrated, whereas bronchial capillaries are fenestrated The appearance of pulmonary venules is identical to that of pulmonary arterioles, and serial sections are required to differentiate the two In contrast with the pulmonary arteries, the larger branches of pulmonary veins not course with the bronchial tree; instead, they are seen within the interlobular septa The media of larger veins is composed of smooth muscle fibers, collagen, and elastin Unlike their arterial counterpart, these veins show no clear internal and external elastic lamina (Fig 41.12) • Fig 41.12  ​Pulmonary vein The media is composed of loose, pale, blue- staining collage fibers with scarce smooth muscle present (Gomori trichrome, 3200.) Bronchial Vascular System Whereas the pulmonary circulation returns all venous blood to the lung and serves some nutritive function to peripheral capillaries, the bronchial circulation is the primary blood source for the lung Although two major bronchial arteries for each lung is a common pattern, this is present less than 40% of the time There usually are two bronchial arteries in the left lung and one in the right lung Although variable, the left bronchial arteries usually arise from the upper portion of the descending aorta The right bronchial artery arises from the descending aorta, one of the right intercostal branches, or subclavian or internal thoracic arteries The bronchial arteries traverse along the dorsal portion of each bronchus They lose their distinctness along the respiratory bronchioles and drain with the alveolar capillaries into the peribronchiolar venous network They form a capillary plexus in the bronchi that supplies the submucosa and muscle The capillary plexus communicates with branches of the pulmonary artery that empty into pulmonary veins Other bronchial arteries supply the interlobular tissue and pleura They drain into the bronchial veins The diameter of the bronchial artery is much smaller than that of the accompanying pulmonary artery It has an internal elastic lamina and media but no external elastic lamina Pulmonary Lymphatics and BronchusAssociated Lymphoid Tissue B A • Fig 41.11  ​Small muscular pulmonary artery (A) traveling with a bronchiole (B) Two layers of smooth muscle cells are present in the vascular media (arrows) (Gomori trichrome, 3200.) Pulmonary lymphatics24 invariably have less elastic tissue in their walls than either arteries or veins.24,25 They are lined by endothelium and valves are present, especially near and in the visceral pleura There are two lymphatic systems in the human lung: a superficial network in the pleura and a deep network around the bronchi and pulmonary arteries and veins and in the connective tissue septa between the pulmonary lobules The two separate systems have anastomoses both in the pleura and near the hilum Lymphatics can be demonstrated to the level of the septal walls but are not found at the alveolar level Lymph flow from both lower lobes drains into the infratracheal lymph nodes The remaining right and left lung lobes drain into the tracheobronchial lymph nodes on each side of the trachea, respectively Lymph ... barrier consists of a 0.1- to 0.2-mm thick septum composed of a capillary endothelial cell and the type I pneumocyte with their intervening fused basal laminae Within thicker portions of the alveolar... covered by thin extensions of alveolar type I (ATI) epithelial cells The capillary (C) is lined by endothelium (E) The epithelium and endothelium rest on a fused basement membrane on the thin portion... in the thick portion of the alveolar wall (35500) prostacyclin, tissue plasminogen activator, and thrombomodulin Other functions include liquid and solid exchange and enzyme activity within the