6 Retinoic Acid Signaling and Development of the Respiratory System
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the proximal airway epithelium. A layer of airway smooth muscle (ASM) cells starts
to form around the most proximal airways (Pringle 1986; Schittny 2017).
The canalicular phase (E16.5 to E17.5 in mice, 17–25 gestation weeks in humans)
is characterized by the continuation of branching. Contrary to the branching pattern
during the pseudoglandular stage, airway branching during the canalicular phase
does not follow a stereotypical pattern (Schittny 2017). The thinning of the distal
epithelium and mesenchyme, and the formation of subepithelial capillaries also occur.
The airways that will transform to alveolar ducts grow in length, appearing like
“canaliculi” (Fig. 6.2). The mesenchymal cells begin to decrease in volume and
number, setting the stage for the formation of the thin air-blood barrier for gas
exchange.
The saccular phase (E17.5 to Post Natal day PN4 in mice, 24–38 gestational
weeks in humans), is marked by the arrest of branching morphogenesis and by the
beginning of alveolarization. The terminal airways, the future gas exchange region,
grow in width and length, forming larger airspaces (“saccules”) (Fig. 6.2). Primary
septa are established when two airspaces meet, lined by the thin type I alveolar cells
which will participate in gas exchange after birth. The remaining surface is covered
by type II alveolar cells, which produce surfactants and serve as progenitors for the
type I epithelial cells. The saccular phase is also marked by the formation of the
primitive capillary network of the respiratory surface and the ongoing thinning of
the interstitium to allow for future gas exchange (Pringle 1986; Schittny 2017).
During the alveolar stage, (PN5 to about PN14-21 in mice, 36 gestation weeks to
10–12 years after birth in humans), the alveoli form by subdivision of the saccules
with secondary alveolar septa and the maturation of the alveolar capillaries. Formation of the secondary alveolar septa generates the first alveoli and further divides
the air spaces, enlarging the surface area for gas exchange (Fig. 6.2) (Pringle 1986;
Schittny 2017).
By young adulthood (completion of lung development), the human lung has a
final gas diffusion surface of 70 m
2 in area and 0.1 μm in thickness that efficiently
exchanges gas and accommodates pulmonary blood flow rates from 4 L/min at rest
to 40 L/min with maximum exercise (Comroe 1965).
Embryonic Development of the Avian Lung
Unlike the mammalian lung, avian lung development does not follow discrete developmental phases (Hsia et al. 2013). The following description refers to the lung
development of the chick embryo (Gallus gallus domesticus), since it is the avian
species most well-studied.
The lung primordium of the chick embryo is discernible as early as E3.5 of incubation, which divides into left and right lung buds that grow towards the body walls.
From E4.0 on, the intrapulmonary primary parabronchi form, while the secondary
bronchi and tertiary parabronchi start to develop from E8.0 and E9.0, respectively.
These parabronchi arise from condensed epithelial cell clusters that subsequently
157
the proximal airway epithelium. A layer of airway smooth muscle (ASM) cells starts
to form around the most proximal airways (Pringle 1986; Schittny 2017).
The canalicular phase (E16.5 to E17.5 in mice, 17–25 gestation weeks in humans)
is characterized by the continuation of branching. Contrary to the branching pattern
during the pseudoglandular stage, airway branching during the canalicular phase
does not follow a stereotypical pattern (Schittny 2017). The thinning of the distal
epithelium and mesenchyme, and the formation of subepithelial capillaries also occur.
The airways that will transform to alveolar ducts grow in length, appearing like
“canaliculi” (Fig. 6.2). The mesenchymal cells begin to decrease in volume and
number, setting the stage for the formation of the thin air-blood barrier for gas
exchange.
The saccular phase (E17.5 to Post Natal day PN4 in mice, 24–38 gestational
weeks in humans), is marked by the arrest of branching morphogenesis and by the
beginning of alveolarization. The terminal airways, the future gas exchange region,
grow in width and length, forming larger airspaces (“saccules”) (Fig. 6.2). Primary
septa are established when two airspaces meet, lined by the thin type I alveolar cells
which will participate in gas exchange after birth. The remaining surface is covered
by type II alveolar cells, which produce surfactants and serve as progenitors for the
type I epithelial cells. The saccular phase is also marked by the formation of the
primitive capillary network of the respiratory surface and the ongoing thinning of
the interstitium to allow for future gas exchange (Pringle 1986; Schittny 2017).
During the alveolar stage, (PN5 to about PN14-21 in mice, 36 gestation weeks to
10–12 years after birth in humans), the alveoli form by subdivision of the saccules
with secondary alveolar septa and the maturation of the alveolar capillaries. Formation of the secondary alveolar septa generates the first alveoli and further divides
the air spaces, enlarging the surface area for gas exchange (Fig. 6.2) (Pringle 1986;
Schittny 2017).
By young adulthood (completion of lung development), the human lung has a
final gas diffusion surface of 70 m
2 in area and 0.1 μm in thickness that efficiently
exchanges gas and accommodates pulmonary blood flow rates from 4 L/min at rest
to 40 L/min with maximum exercise (Comroe 1965).
Embryonic Development of the Avian Lung
Unlike the mammalian lung, avian lung development does not follow discrete developmental phases (Hsia et al. 2013). The following description refers to the lung
development of the chick embryo (Gallus gallus domesticus), since it is the avian
species most well-studied.
The lung primordium of the chick embryo is discernible as early as E3.5 of incubation, which divides into left and right lung buds that grow towards the body walls.
From E4.0 on, the intrapulmonary primary parabronchi form, while the secondary
bronchi and tertiary parabronchi start to develop from E8.0 and E9.0, respectively.
These parabronchi arise from condensed epithelial cell clusters that subsequently