Development of the Respiratory
System and Birth
The embryological origins of
the lung are primitive endoderm of the foregut, which eventually forms
the epithelium and glands of the larynx, trachea and lungs, and splanchnic
mesoderm, which forms cartilage, smooth muscle, lung parenchyma and
connective tissue. In common with many glandular organs, the lung develops by branching morphogenesis (Fig. 16a), with budding and branching of the
endoderm/epithelium into mesoderm. The process requires reciprocal signalling
between epithelium and mesoderm, with the mesoderm being primarily
responsible for programming development of adjacent epithelium into the
relevant structures. Many signalling molecules are vital for the orchestration
of branching morphogenesis during lung development, including growth factors
such as fibroblast growth factor (FGF), epidermal growth factor (EGF) and
platelet-derived growth factor (PDGF); vascular endothelial growth factor
(VEGF) is critical for pulmonary vascular development. Development of the
respiratory system is generally divided into five stages or periods.
1. Embryonic
period: The tracheobronchial tree
originates from the laryngotracheal tube, below the fourth pharyngeal
pouch at the caudal (tail) end of the primordial pharynx. The laryngotracheal
tube starts to appear just prior to the fourth week of development, after the heart
begins to beat. By the end of the fourth week, its end has bifurcated into two bronchial
buds, progenitors of the two main bronchi and bronchial tree (Fig. 16b).
2. Pseudoglandular
period (5-17th weeks): The bronchial
buds have now developed into the primordial left and (slightly larger) right
primary bronchi, which subsequently divide by branching morphogenesis into five
secondary bronchi (three right, two left). At the seventh week, these have started
to branch progressively into ten (right) or eight to nine (left) segmental (tertiary)
bronchi, each of which eventually forms a bronchopulmonary segment. By the
17th week, most major structures of the lung have formed and are lined with columnar
epithelial cells. Conducting blood vessels are present, but the gas exchange
surfaces have not yet developed and fetuses delivered during this period are therefore
not viable.
3. Canalicular
period (16-25th weeks): Bronchial
cartilage, smooth muscle, pulmonary capillaries and connective tissue develop
from the mesoderm. There is progressive differentiation and thinning of epithelial
cells. The bronchi will have subdivided approximately 17 times after 24 weeks,
finall forming the respiratory bronchioles which themselves divide into three
to six alveolar ducts and some thin-walled terminal sacs. These are
lined by very thin type I alveolar pneumocytes (squamous epithelium),
which together with endothelial cells from capillaries form the future alveolocapillary
membrane (gas exchange surface). There are a few type II alveolar
pneumocytes, secretory epithelial cells that produce surfactant. This
reduces surface tension and allows expansion of the terminal sacs/alveoli
(Chapter 6), but although it is present in small amounts from about the 20th
week, there is insuf- ficien to support unaided breathing until after 26 weeks
(see neonatal respiratory distress syndrome, Chapter 17). Some gas
exchange can occur at the end of this period, as there are both thin-walled terminal
sacs and good vascularization, but the general level of immaturity means that
fetuses born before the end of the 24th week normally die despite intensive care.
4. Saccular
(terminal sac) period (24th week
to parturition): Associated with rapid development in the number of terminal
sacs and the pulmonary and lymphatic capillary networks. Budding from terminal
sacs and walls of terminal bronchioles and thinning of type I pneumocytes lead
to formation of immature alveoli from around week 32. Suff cient surfactant and
vascularization are normally present between the 24 and 26th week to allow
survival of some premature fetuses, although this is very variable (Chapter 17).
Surfactant increases significantly in the 2 weeks before birth.
5. Alveolar
period (late fetal to childhood):
Clusters of immature alveoli form during the early part of this period;
mature-type alveoli with thin interalveolar septa and gas exchange surfaces do
not appear until after birth. Fetal breathing movements are present
before birth, with aspiration of amniotic fluid and these stimulate lung growth
and respiratory muscle conditioning. Lung development is impaired in the absence
of fetal breathing, inadequate amniotic flui (oligohydramnios) or
space for lung growth (Chapter 17). The increase in lung size over the firs 3
years is due primarily to an increase in number of alveoli and respiratory
bronchioles; thereafter, both the number and size of alveoli increase. More
than 90% of alveoli are formed after birth, reaching a maximum after 7-8 years.
At the end of lung development, there are approximately 23 generations of
airways, with approximately 17 million branches.
Fetal circulation and birth
Gas exchange in the fetus occurs in
the placenta. Oxygen-rich blood from the umbilical vein fl ws into the
liver and ductus venosus, and thus into the vena cava. Most blood
entering the right atrium is diverted into the left atrium via the foramen
ovale; the remainder enters the right ventricle and is pumped into the
pulmonary artery as in the adult (Fig. 16c). However, the vascular resistance
of the pulmonary circulation is high due to the collapsed state of the lungs
and vasoconstriction, and 90% of the blood is therefore shunted via the ductus
arteriosus into the aorta (Fig. 16c). Note that the Pao2
in the fetus is much lower ( 4 kPa, 30 mmHg) than in the adult; oxygen
transport is sustained by high-affinit fetal haemoglobin (Chapter 8).
At birth, the lungs are initially 50% full of flui which
is replaced by air. During and immediately following birth, flui is removed via
the pulmonary and lymphatic circulations, and through the mouth as a result of
squeezing during delivery. Expansion and fillin of the alveoli with air is
critically dependent on the presence of surfactant to lower surface
tension. The initiation of gas exchange in the lungs and consequent rise in
blood Po2 cause vasodilatation of the pulmonary circulation
and constriction of the ductus arteriosus, so that blood from the right side of
the heart now follows its adult course via the lungs. The consequent fall in
right atrial pressure causes the pressure gradient across the foramen ovale to
reverse, causing functional closure within hours. The removal of venous return
from the placenta also causes closure of the ductus venosus. Initially,
pressure gradients keep the three fetal shunts closed, but after several months
structural changes cause permanent closure. In 20% of adults this may remain
incomplete for the foramen ovale, but is generally of no consequence.
