·0 When the embryo is approximately 4 weeks old the respiratory diverticulum (lung bud)

appears as an outgrowth from the ventral wall of the foregut (Fig. 14.1A).
·1 The appearance and location of the lung bud are dependent upon an increase in
retinoic acid (RA) produced by adjacent mesoderm.
·2 This increase in RA causes upregulation o f the transcription factor TBX4 expressed in the
endoderm o f the gut tube at the site o f the respiratory diverticulum.
·3 TBX4 induces formation of the bud and the continued growth and differentiation of the
lungs.
·4 Hence, epithelium of the internal lining of the larynx,trachea, and bronchi, as well as
that of the lungs, is entirely of endodermal origin.
·5 The cartilagenous, muscular and connective tissue components of the trachea and
lungs are derived from splanchnlc mesoderm surrounding the foregut.
·6 Initially, the lung bud is in open communication with the foregut (Fig. 14.1B).
·7 When the diverticulum expands caudally, however, two longitudinal ridges, the
tracheoesophageal rldges, separate it from the foregut (Fig. 14.2A).
·8
 9. Subsequently, when these ridges fuse to form the tracheoesophageal septum, the
foregut is divided into a dorsal portion, the esophagus, and a ventral portion, the
trachea and lung buds (Fig. 14.2B,C)
·9 The respiratory primordium maintains its communication with the pharynx through the
laryngeal orífice (Fig. 14.2D).
·10 LARYNX- The internal lining o f the larynx originates from endoderm, but the cartilages
and muscles origínate from mesenchyme of the fourth and sixth pharyngeal arches.
·11

As a result of rapid proliferation, of this mesenchyme, the laryngeal orifice changes in

appearance from a sagittal slit to a T-shaped opening (Fig. 14.4A)
·12 Subsequently, when mesenchyme of the two arches transforms into the thyroid, cricoid,
and arytenoid cartilages the characteristic adult shape of the laryngeal orifice can be
recognized (Fig. 14.4B)
·13 At about the time that the cartilages are formed, the laryngeal epithelium also
proliferates rapidly, resulting in a temporary occlusion of the lumen.
·14 Subsequently, vacuolization and recanalization produce a pair of lateral recesses, the
laryngeal ventricles.
·15 These recesses are bounded by folds of tissue that diíferentiate into the false and true
 vocal cords.
·16 Because musculature of the larynx is derived from mesenchyme of the fourth and sixth
pharyngeal arches, all laryngeal muscles are innervated by branches of the tenth cranial
nerve, the vagus nerve: The superior laryngeal nerve innervates derivatives of the
fourth pharyngeal arch, and the recurrent laryngeal nerve innervates derivatives of the
sixth pharyngeal arch.
·17 During its separation from the foregut, the lung bud forms the trachea and two lateral
outpocketings the bronchial buds (Fig. 14.2B,C)
·18 At the beginning of the 5th week, each of these buds enlarges to form right and left
main bronchi.
·19 The right then forms three secondary bronchi, and the left, two (Fig. 14.5A), thus
foreshadowing the three lobes of the lung on the right side and two on the left (Fig.
14.5fí,C)
·20

·21 With subsequent growth in caudal and lateral directions, the lung buds expand into the
body cavity (Fig. 14.6)
·22 The spaces for the lungs, the pericardioperitoneal canals, are narrow. They lie on each
side of the foregut and are gradually filled by the expanding lung buds.
·23
·24 Ultimately, the pleuroperitoneal and pleuropericardial folds separate the
pericardioperitoneal canals from the peritoneal and pericardial cavities, respectively, and
the remaining spaces form the primitive pleural cavities.
·25 The mesoderm, which covers the outside of the lung, develops into the visceral pleura
·26 The somatic mesoderm layer, covering the body wall from the inside, becomes the
parietal pleura (Fig. 14.6A).
·27 The space between the parietal and visceral pleura is the pleural cavity (Fig. 14.7).
·28
·29 During further development, secondary bronchi divide repeatedly in a dichotomous
fashion forming 10 tertiary (segmental) bronchi in the right lung and 8 in the left,
creating the bronchopulmonary segments of the adult lung.
·30 By the end o f the sixth month, approxrmately 17 generations of subdivisions have
formed.
·31 Before the bronchial tree reaches its final shape, however, an additional six divisions
form during postnatal life.
·32 Branching is regulated by epithelial-mesenchymal interactions between the endoderm
of the lung buds and splanchnic mesoderm that surrounds them.
·33 Signals for branching, which emit from the mesoderm, involve members of the fibroblast
growth factor (FGF) family.
·34 While all o f these new subdivisions are occurring and the bronchial tree is developing,
the lungs assume a more caudal position, so that by the time of birth, the bifiircation of
the trachea is opposite the fourth thoracic vertebra.
·35 Up to the 7th prenatal month, the bronchioles divide continuously into more and
smaller canals (canalicular phase) and the vascular supply increases steadily (Fig. 14.8A).
·36 Terminal bronchioles divide to form respiratory bronchioles, and each of these divides
into three to six alveolar ducts (Fig. 14.8B)
·37 The ducts end in terminal sacs (primitive alveoli) that are surrounded by flat alveolar
cells in close contact with neighboring capillaries (Fig. 14.85)
·38
·39 By the end o f the 7th month, sufficient numbers of mature alveolar sacs and capillaries
 are present to guarantee adequate gas exchange, and the premature infant is able to
sundve (Fig. 14.9) table

·40
·41

·42 During the last 2 months of prenatal life and for several years thereafter, the number of
terminal sacs increases steadily.
·43 In addition, cells lining the sacs, known as type I alveolar epithelial cells, become
thinner, so that surrounding capillaries protrude into the alveolar sacs (Fig. 14.9).
·44 This intímate contact between epithelial and endothelial cells makes up the blood-air
barrier.
·45 Mature alveoli are not present before birth.
·46 In addition to endothelial cells and flat alveolar epithelial cells, another cell type
develops at the end of 6thy month.
·47 These cells, type II alveolar epithelial cells, produce surfactant, a phospholipid-rich fluid
capable of lowering surface tension at the air-alveolar interface.
 ·48 Before birth, the lungs are full o f fluid that contains a high chloride concentration, little
protein, some mucus from the bronchial glands, and surfactant from the alveolar
epithelial cells (type II).
·49 The amount of surfactant in the fluid increases, particularly during the last 2 weeks
before birth.
·50 As concentrations o f surfactant increase during the 34th week of gestation, some of this
phospholipid enters the amniotic fluid and acts on macrophages in the amniotic cavity.
·51 Once “activated" evidence suggests that these macrophages migrate across the chorion
into the uterus where they begin to produce immune system proteins, including
ínterleukin-1B (IL -lB ).
·52 Upregulation of these proteins results in increased production of prostaglandins that
cause uterine contractions.Thus, there may be signáis from the fetus that particípate in
initiating labor and birth.
·53 Fetal breathíng movements begin before birth and cause aspiration of amniotic
fluid.These movements are important for stimulating lung development and
conditioning respiratory muscles.
·54 When respiration begins at birth, most of the lung fluid is rapidly resorbed by the blood
and lymph capillaries, and a small amount is probably expelled via the trachea and
bronchi during delivery.
·55 When the fluid is resorbed from alveolar sacs, surfactant remains deposited as a thin
phospholipid coat on alveolar cell membranes.
·56 With air entering alveoli during the first breath,the surfactant coat prevents
development of an air-water (blood) interface with high surface tension.
·57 Without the fatty surfactant layer, the alveoli would collapse during expiration
(atelectasis).
·58 Respiratory movements after birth bring air into the lungs, which expand and flll the
pleural cavity. Although the alveoli increase somewhat in size, growth of the lungs after
birth is due primarily to an increase in the number of respiratory bronchioles and
alveoli.
·59 It is estimated that only one-sixth o f the adult number of alveoli are present at birth.
The remaining alveoli are formed during the first 10 years of postnatal life through the
continuous formation of new primitive alveoli.

SUMMARY
The respiratory system is an outgrowth of the ventral wall o f the foregut, and the epithelium of
the larynx, trachea, bronchi, and alveoli originales in the endoderm. The cartilaginous, muscular,
and connective tissue components arise in the mesoderm. In the fourth week of development,
the tracheoesophageal septum separates the trachea from the foregut, dividing the foregut into
the lung bud anteriorly and the esophagus posteriorly. Contact between the two is maintained
through the larynx, which is formed by tissue of the fourth and sixth pharyngeal arches. The lung
bud develops into two main bronchi: The right forms three secondary bronchi and three lobes;
the left forms two secondary bronchi and two lobes. Faulty partitioning of the foregut by the
tracheoesophageal septum causes esophageal atresias and tracheoesophageal fístulas (TEFs).
After a pseudoglandular (5 to 16 weeks) and canalicular (16 to 26 weeks) phase, cells of the
cuboidal-lined respiratory bronchioles change into thin, flat cells, type I alveolar epithelial cells,
intimately associated with blood and lymph capillaries. In the seventh month, gas exchange
between the blood and air in the primitive alveoli is possible. Before birth, the lungs are filled
with fluid with littie protein, some mucus, and surfactant, which is produced by type II alveolar
epithelial cells and which forms a phosphoUpid coat on the alveolar membranes. At the
beginning o f respiration, the lung fluid is resorbed except for the surfactant coat, which prevenís
the collapse of the alveoli during expiration by reducing the surface tensión at the air-blood
capillary interface. Absent or insufficient surfactant in the premature baby causes respiratory
distress syndrome(RDS) because o f collapse of the primitive alveoli (hyaline membrane disease).
Growth of the lungs after birth is primarily due to an increase in the number o f respiratory
bronchioles and alveoli and not to an increase in the size of the alveoli. New alveoli are formed
during the flrst 10 years of postnatal life.
Probletns to Solve
1. A prenatal ultrasound revealed polyhydramnios, and at birth, the baby had excessive fluids in
its mouth. W hat type o f birth defect might be present, and what is its embryological origin?
Would you examine the child carefully for other birth defects? Why?
2. A baby born at 6 months’ gestation is having trouble breathing. Why?