The lower respiratory organs (larynx, trachea, bronchi, and lungs) begin to form during the fourth week of development.
Respiratory Primordium
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The respiratory system starts as a median outgrowth, the laryngotracheal groove , which appears in the floor of the caudal end of the anterior foregut (primordial pharynx) ( Fig. 10.1 B and C ; see also Fig. 10.4 A ). This primordium of the tracheobronchial tree develops caudal to the fourth pair of pharyngeal pouches. The endodermal lining of the laryngotracheal groove forms the pulmonary epithelium and glands of the larynx, trachea, and bronchi. The connective tissue, cartilage, and smooth muscle in these structures develop from splanchnic mesoderm surrounding the foregut (see Fig. 10.5 A ).
By the end of the fourth week, the laryngotracheal groove has evaginated (protruded) to form a pouch-like laryngotracheal diverticulum , which is located ventral to the caudal part of the foregut ( Fig. 10.2 A , and see also Fig. 10.1 B ). As this diverticulum elongates, it is invested with splanchnic mesenchyme . Its distal end enlarges to form a globular respiratory bud (lung bud) that denotes the single bud from which the tracheobronchial (respiratory) tree originates (see Fig. 10.2 B ). The right and left lung buds first appear as two lateral outpouchings of the foregut on either side of the tracheal primordium.
The laryngotracheal diverticulum soon separates from the primordial pharynx; however, it maintains communication with it through the primordial laryngeal inlet (see Fig. 10.2 C ). Longitudinal tracheoesophageal folds develop in the diverticulum, approach each other, and fuse to form a partition, the tracheoesophageal septum , at the end of the fifth week (see Fig. 10.2 D and E ). This septum divides the cranial portion of the foregut into a ventral part, the laryngotracheal tube (the primordium of the larynx, trachea, bronchi, and lungs), and a dorsal part (the primordium of the oropharynx and esophagus; see Fig. 10.2 F ). The opening of the laryngotracheal tube into the pharynx becomes the primordial laryngeal inlet (see Figs. 10.2 C and 10.4 B to D ). The separation of the single foregut tube into the trachea and esophagus results from a complex and coordinated process of multiple signaling pathways and transcription factors ( Fig. 10.3 ).
Development of Larynx
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The epithelial lining of the larynx develops from the endoderm of the cranial end of the laryngotracheal tube (see Fig. 10.2 C ). The cartilages of the larynx develop from the fourth and sixth pairs of pharyngeal arches (see Fig. 10.1 A and C ). The laryngeal cartilages develop from mesenchyme that is derived from neural crest cells . The mesenchyme at the cranial end of the laryngotracheal tube proliferates rapidly, producing paired arytenoid swellings ( Fig. 10.4 B ). The swellings grow toward the tongue, converting the slit-like aperture, the primordial glottis , into a T -shaped laryngeal inlet and reducing the developing laryngeal lumen to a narrow slit (see Fig. 10.4 C ).
The laryngeal epithelium proliferates rapidly, resulting in temporary occlusion of the laryngeal lumen. Recanalization normally occurs by the 10th week (see Fig. 10.4 D ); laryngeal ventricles form during this recanalization process. These recesses are bounded by folds of mucous membrane that become the vocal folds (cords) and vestibular folds .
The epiglottis develops from the caudal part of the hypopharyngeal eminence, a prominence produced by proliferation of mesenchyme in the ventral ends of the third and fourth pharyngeal arches (see Fig. 10.4 B to D ). The rostral part of this eminence forms the posterior third or pharyngeal part of the tongue (see Fig. 10.4 C and D ).
Because the laryngeal muscles develop from myoblasts in the fourth and sixth pairs of pharyngeal arches, they are innervated by the laryngeal branches of the vagus nerves (cranial nerve X) that supply these arches (see Chapter 9 , Table 9.1 ). The larynx is found in a high position in the neck of the neonate; this positioning allows the epiglottis to come into contact with the soft palate. This provides an almost separate respiratory and digestive tract, facilitating nursing, but also means that neonates almost obligatorily breathe through their noses. Structural descent of the larynx occurs over the first 2 years of life.
Laryngeal atresia (obstruction) , a rare birth defect, results from failure of recanalization of the larynx, which produces obstruction of the upper fetal airway, or congenital high airway obstruction syndrome (CHAOS syndrome) . Distal to the region of atresia or stenosis (narrowing), the fetal airways become dilated, and the lungs are enlarged and filled with fluid. The diaphragm is either flattened or inverted, and there is an accumulation of serous fluid in the peritoneal cavity (fetal ascites) in the intracellular spaces, causing severe edema (hydrops). CHAOS syndrome is very often fatal due to fetal heart failure. In some less severe cases, postpartum airway intervention (tracheostomy) may lead to survival.
Incomplete atresia, or laryngeal web, is a defect in which the connective tissue between the vocal folds is covered with a mucous membrane; this causes airway obstruction and a hoarse cry in the neonate. This defect results from incomplete recanalization of the larynx during the 10th week. Treatment is by endoscopic dilation of the laryngeal web.
Development of Trachea
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During its separation from the foregut, the laryngotracheal diverticulum forms the primordium of the trachea and two lateral outpouchings, the primary bronchial buds (see Figs. 10.2 C , 10.8 A , and 10.9 ). The endodermal lining of the laryngotracheal tube distal to the larynx differentiates into the epithelium and glands of the trachea and the pulmonary epithelium. The cartilage, connective tissue, and muscles of the trachea are derived from the splanchnic mesenchyme surrounding the laryngotracheal tube ( Fig. 10.5 ). The cargo receptor Evi/Wis is involved in the dorsal-ventral patterning of the endodermal lining of the laryngotracheal tube. Proliferation of the surrounding mesenchyme and formation of cartilage and muscles are regulated by Wnt/β−catenin signaling pathways.
A fistula (abnormal passage) between the trachea and esophagus occurs once in 3000 to 4500 infants ( Figs. 10.6 and 10.7 ); most affected infants are males. In more than 85% of cases, the tracheoesophageal fistula (TEF) is associated with esophageal atresia . A TEF results from incomplete division of the cranial part of the foregut into respiratory and esophageal parts during the fourth week. Incomplete fusion of the tracheoesophageal folds results in a defective tracheoesophageal septum and a TEF between the trachea and esophagus.
TEF is the most common birth defect of the lower respiratory tract. Four main varieties of TEF may develop (see Fig. 10.6 ). The usual defect is for the superior part of the esophagus to end blindly (esophageal atresia) and for the inferior part to join the trachea near its bifurcation (see Figs. 10.6 A and 10.7 ). Other varieties of this defect are illustrated in Fig. 10.6 B to D .
Infants with the common type of TEF and esophageal atresia cannot swallow, so they frequently drool saliva and immediately regurgitate milk when fed. Gastric and intestinal contents may also reflux from the stomach through the fistula into the trachea and lungs. This refluxed acid, and in some cases bile, can cause pneumonitis (inflammation of the lungs), leading to respiratory compromise. Polyhydramnios is often associated with esophageal atresia. The excess amniotic fluid develops because fluid cannot enter the stomach and intestines for absorption and subsequent transfer through the placenta to the mother’s blood for disposal.
Uncommonly, the larynx and upper trachea may fail to separate completely from the esophagus. This results in a persistent connection of variable lengths between these normally separated structures, or laryngotracheoesophageal cleft . Symptoms of this birth defect are similar to those of TEF because of aspiration of fluid and/or food into the lungs. Aphonia (inability to speak) is a distinguishing feature.
Stenosis (narrowing) and atresia of the trachea are uncommon birth defects, which are usually associated with one of the varieties of TEF. Stenoses and atresias probably result from unequal partitioning of the foregut into the esophagus and trachea (see Fig. 10.6 ). Sometimes there is a web of tissue obstructing airflow (incomplete tracheal atresia) . Atresia or agenesis (absence) of the trachea is uniformly fatal.
Tracheal diverticulum , or bronchus , consists of a blind, bronchus-like projection from the trachea. The outgrowth may terminate in normal-appearing lung tissue, forming a tracheal lobe of the lung. This diverticulum may cause recurrent infection and respiratory distress in infants.
Development of Bronchi and Lungs
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A respiratory bud (lung bud) develops at the caudal end of the laryngotracheal diverticulum during the fourth week (see Fig. 10.2 A and B ). The bud soon divides into two outpouchings, the primary bronchial buds ( Figs. 10.8 A and 10.9 , and see Fig. 10.2 C ). These buds grow laterally into the pericardioperitoneal canals , the primordia of the pleural cavities (see Fig. 10.8 B ). Secondary and tertiary bronchial buds soon develop.
