Learning aims www.embryology.ch/indexen.

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At the end of this module you should be able to:

know the various prenatal stages of lung development. be able to list and localize the various cells that are typical for lung tissue. know the components of the blood-air barrier. be able to describe the development of the various somatic cavities. know where the pericardio-peritoneal duct lies. know the difference between the vasa publica and privata in the lungs. be able to explain the occurrence of fistulas between the esophagus and trachea based on your knowledge of the development of the two structures. know the various mechanisms in charge of the switch of the circulation systems at birth.

What you should already know

Embryogenesis Cardiovascular system

Introduction
The respiratory system starts to develop with an inconspicuous laryngotracheal groove (stage 10, ca. 28 days, 10 ) that forms in the ventral midline at the lower end of the pharynx. The caudal part of this groove develops into the lung anlage in that it divides into right and left lung buds (stage 12, ca. 30 days, 12 ). The upper part of this groove remains undivided and becomes the trachea. The two lung buds extend and form the main bronchus (stage 14, ca. 33 days, 14 ). These subdivide further and form 2 (on the left side) and 3 (on the right) lobular buds and thus the lobular bronchi. The whole lung development takes place in five main phases that partially overlap (4); followed by a maturation stage:

Embryonic phase (3rd - 8th week) Pseudoglandular phase (5th - 17th week) Canalicular phase (16th - 26th week) Saccular phase (24th week up to birth) Alveolar phase (36th week up to the 18th month post partum) Stage of the microvascular maturation (from birth to 2 - 3 years) Fig. 1 - Overview of the intrauterine phases of lung development

Adult lungs have an inner surface area of 140 m2. This extent can only be achieved through an enormous increase in the inner complexity of the pulmonary parenchyma. This is described in the following chapters.

Delving deeper

Why does a laryngo-tracheal groove form in the ventral part of the foregut? What are the mechanisms underlying the dichotomous division of the bronchi?

Why does further branching normally occur distally in the bronchial tree and not in the trachea? Quiz Embryonic phase Quiz 02 The embryonic phase of lung development begins with the formation of a groove in the ventral lower pharynx, the sulcus laryngotrachealis (stage 10, ca. 28 days, 10 ). After a couple of days - from the lower part - a bud forms, the true lung primordium (stage 12, ca. 30 days, 12 ). In Quiz Quiz 11

the further subdivision into the two main bronchi (stage 14, ca. 33 days, 14 ) the smaller bud on the left is directed more laterally than the somewhat larger one on the right that - parallel to the esophagus - is directed more caudally. Thus the asymmetry of the main bronchi, as they present in adults, is already established. The subsequent divisions of the endodermal branches also take place unequally in that on the right three further buds form and, on the left, only two, corresponding to the later pulmonary lobes. In the next division step, which occurs at the end of the embryonic period, the segments of the individual pulmonary lobes arise. More info It appears that the branching and growth of the lung anlage is under the direction of the mesenchyma on which it lies. Like in the kidney, it appears also here that an epithelio-mesenchymal interaction is important for the normal development of the lungs. This is shown by recombination experiments in which the tracheal epithelium begins to fork when it is grown on a layer of bronchial mesenchyma. (6) . At the end of the embryonic period the first segments appear in the five (three right and two left) lobes of the lungs. With their distended ends the lungs resemble an exocrine gland. At this time the pulmonary vessels have formed themselves.

Quiz Quiz 03

Development of the lungs up to the end of the embryonic period 1 2 3 4 5 6 7 Right main bronchus Upper right pulmonary lobe Middle pulmonary lobe Lower right pulmonary lobe Left main bronchus Upper left pulmonary lobe Lower left pulmonary lobe

The pulmonary circulation system (smaller circulation system) is formed out of the 6th pharyngeal arch artery. These develop somewhat differently than the other 4 aortic arches in that first a vessel plexus forms around the lung anlage, originating from the aortic sac. The true 6th aortic arch is only then formed after vessels - also from the dorsal aorta grow into this plexus and thus a connection between the truncus pulmonalis and dorsal aorta has arisen. Fig. 3 - Development of the pulmonary vessels in stage 13 Fig. 4 - Development of the pulmonary vessels in stage 15 Legend Fig. 3 From the aortic sac a vessel plexus arises around the lung anlagen that with the lung buds extends caudally. Fig. 4 Also from the dorsal aorta a vessel plexus forms that soon communicates with the ventral one and thus creates a connection between the ventral aortic sac and the dorsal

1 First aortic arch (atrophying) 2 Second aortic arch 3 Third aortic arch (internal carotid artery forms from the 4 ventral part) Fourth aortic arch (on the right: part of the subclavian artery, left: arcus aortae)

5 6 7 8

Dorsal aorta Lung buds Aortic sac Pulmonary plexus

Pseudoglandular phase
At this stage the lungs resemble the development of a tubulo-acinous gland. According to the classical view, the entire air-conducting bronchial tree up to the terminal bronchioli are set down in this phase (16 generations). Recent morphometric studies (3) have shown that with the end of the pseudoglandular phase 20 generations are partially present in the lungs, which means that at this point in time the respiratory ducts have already been formed. The primordial system of passages, the air-conducting bronchial tree, is initially coated by cubic epithelium. These are the precursor cells of the ciliated epithelium and of the secretory cells. In humans, the first ciliated epithelial cells can be found in the 13th week of pregnancy (7). In the respiratory part the first typically lung-specific cells, connected to the terminal bronchioli, appear: the type II pneumocytes (alveolar cells) (3). The developing bronchopulmonary epithelium begins to produce amniotic fluid, which is also found in the lungs up to the time of birth. Fig. 5 - Lung tissue in the pseudoglandular phase

aorta. On the left the arterial duct arises from it. Quiz Quiz 04

Legend Fig. 5 In the pseudoglandular phase the lungs resemble a gland. At the end of this phase the precursors of the pneumocytes can be discerned in the respiratory sections as cubic epithelium.

1 Lung mesenchyma 2 Type II pneumocytes 3 Capillaries

More info Relatively early in the development of the lungs, endocrine-active cells (Kultschitsky cells) appear that produce bombesin and serotonin. In contrast to the precursors of the pneumocytes, which originate from the endoderm, they stem from the neural crest (neuroectoderm). Via

paracrine mechanisms bombesin probably plays a decisive role for lung development in that mainly the type II pneumocytes proliferate. (1) The differentiation of the lungs takes place in a centrifugal direction. In the central, air-conducting portions of the lungs the epithelium begins to differentiate into cilia-carrying cells and goblet cells. After the 10th week cartilage and smooth muscle cells as well as bronchial glands can be found in the wall of the bronchi. The peripheral sections partially retain - until far beyond the pseudoglandular phase - cubic epithelium that is still little differentiated. This is important for a further proliferation of the bronchial tree into the surrounding mesenchymal tissue. More info If one begins, roughly estimated, with a number of 15'000 terminal bronchioli (8) per lung in adults and thereby ca. 15,000 acini and with a theoretical assumption of a dichotomous division of the pulmonary branches, one has the result that this stage is attained after little fewer than 2 14 generations. In the late pseudoglandular stage one finds, however, far more than 15'000 end pieces. Thus the lung end pieces at this stage already represent the respiratory portions of the lungs.

Canalicular phase
In the classical description of lung development, in this phase the canaliculi branch out of the terminal bronchioli. The canaliculi compose the proper respiratory part of the lungs, the pulmonary parenchyma. All of the air spaces that derive from a terminal bronchiolus form an acinus. Each one comprises respiratory bronchioli and the alveolar ducts and later the alveolar sacculi. The chief characteristic of this canalicular phase is the alteration of the epithelium and the surrounding mesenchyma. Along the acinus, which develops from the terminal bronchiolus, an invasion of capillaries into the mesenchyma occurs. The capillaries surround the acini and thus form the foundation for the later exchange of gases. The lumen of the tubules becomes wider and a part of the epithelial cells get to be flatter. From the cubic type II pneumocytes develop the flattened type I pneumocytes. A sufficient differentiation of the type II pneumocytes into the type I Fig. 6 - Lung tissue in the canalicular phase More info Histological image of the canalicular phase of lung development

Legend

pneumocytes and the proliferation of the capillaries into the mesenchyma marks an important step towards the fetus being able to survive outside the uterus after roughly the 24th week of pregnancy.

Fig. 6 The type I pneumocytes differentiate out of the type II pneumocytes. The capillaries approach the walls of the acini. 1 Type I pneumocytes 2 Type II pneumocytes 3 Capillaries

More info The first breathing movement can be registered already at the end of the embryonic period. They are controlled by a breathing center in the brain stem. Nevertheless, these breathing movements are paradoxical in that when the diaphragm contracts, the thorax moves inwardly and vice versa. (2) At the end of this canalicular phase which is the beginning of the saccular phase (ca. 25 weeks) - a large part of the amniotic fluid is produced by the lung epithelium. From this time on, the maturity of the lungs can be measured clinically based on the activity of the type II pneumocytes, which begin to produce the surfactant. The ratio of lecithin to sphingomyelin in the amniotic fluid, which increases with fetal age is determined. I In this stage developmental damage already affects the gas-exchange components and result in structural alterations of the later pulmonary parenchyma. More info The surfactant (abbreviation for surface active agent) consists of glycerophospholipids, specific proteins, neutral fats and cholesterol. It covers the alveolar surface and reduces the surface tension so that, following birth, the alveoli do not collapse during the expiration.

Saccular phase

Quiz Quiz 05

From the last trimester whole clusters of sacs form on the terminal bronchioli, which represent the last subdivision of the passages that supply air. In the saccular phase the last generation of air spaces in the respiratory part of the bronchial tree is born. At the end of each respiratory tract passage smooth-walled sacculi form, coated with type I and type II pneumocytes. The septa (primary septa) between the sacculi are still thick and contain two networks of capillaries that come from the neighboring sacculi. The interstitial space is rich with cells and the proportion of collagen and elastic fibers is still small. This matrix, though, plays an important role for the growth and differentiation of the epithelium that lies above it (9). At the end of this phase the interstitial fibroblasts begin with the production of extracellular material in the interductal and intersaccular space. Fig. 7 - Histological scheme of the saccular phase Fig. 8 - Blood-air barrier in the lung Legend Fig. 7 The capillaries multiply around the acini. They push close to the surface and form a common basal membrane with that of the epithelium. Fig. 8 The bloodair barrier in the lungs is reduced to three, thin layers: type I pneumocyte, fusioned basal membrane, and

1 Type I pneumocyte 2 Type II pneumocyte 3 Capillaries

1 2 3 4 5 6

Type I pneumocyte Saccular space Type II pneumocyte Basal membrane of the air passage Basal membrane of the capillaries Endothelium of the capillaries

endothelium of the capillary. At birth, i.e., at the end of the saccular phase, all generations of the conducting and respiratory branches have been generated. The sacculi are thin, smooth-walled sacks and correspond to the later alveolar sacculi.

Alveolar phase
Depending on the author, the alveolar phase begins at varying times. Probably in the last few weeks of the pregnancy, new sacculi and, from them, the first alveoli form. Thus, at birth, ca. 1/3 of the roughly 300 million alveoli should be fully developed. The alveoli, though, are only present in their beginning forms. Between them lies the parenchyma, composed of a double layer of capillaries, that forms the primary septa between the alveolar sacculi. Fig. 9 - Alveolar phase before birth Legend Fig. 9 In the alveolar phase the alveoli form from the terminal endings of the alveolar sacculi and with time increase their diameter.

1 2 3 4 5 6

Alveolar duct Primary septum Alveolar sac Type I pneumocyte Type II pneumocyte Capillaries

Already before birth these alveolar sacculi get to be increasingly complex structurally. Thereby, a large number of small protrusions form along the primary septa. Soon, these become larger and subdivide the sacculi into

smaller subunits, the alveoli, which are delimited by secondary septa. Ultrastructural investigations show that overall where such alveoli appear, they are surrounded by elastic fibers that form the interstitial septa between two capillary nets. In the first 6 months, their number increases massively. This "alveolarization" and therewith the formation of secondary septa should - to a limited extent still - continue up to the first year and a half of life. Fig. 10 - Alveolar phase following birth Legend Fig. 10 In the alveolar phase after birth more and more alveoli form from the terminal endings of the alveolar sacculi and with time increase in diameter. They are delimited by secondary septa.

1 2 3 4 5 6

Alveolar duct Secondary septum Alveoli Type I pneumocyte Type II pneumocyte Capillaries

Classification in the adult lung

In the adult lung one distinguishes between conducting and respiratory zones. In the conducting zone, all branches of the bronchial tree, the walls of which contain cartilage tissue and seromucous glands, are bronchi. As soon as cartilage and glands are no longer present, bronchioli are involved. Fig. 11 - Overview of the wall construction in the lungs

Quiz Quiz 06 Quiz Quiz 13 Quiz Quiz 07 Legend

Fig. 11 Diagrams for comparing the constructions of the walls in the respiratory tract.

1 Ciliated epithelium 2 Goblet cell 3 Gland 4 Cartilage 5 Smooth muscle cell 6 Clara cell 7 Capillary 8 Basal membrane 9 Surfactant 10 Type I pneumocyte 11 Alveolar septum 12 Type II pneumocyte According to their function the respiratory tract passages are divided into conducting and respiratory zones: Conducting zone = 16 generations

Segmental bronchi are continued by several generations of Intersegmental bronchi (up to ca. 1 mm diameter). After these follow the Bronchioli (< 1mm diameter) that after several divisions go over into

More info Histological image of respiratory epithelium.

Terminal bronchioli (ca. 0.4 mm diameter). They subdivide numerous times and represent the end stretch of the purely conductive respiratory tract. The measurements come from histological findings. Respiratory zone = 7 generations

More info

Out of the terminal bronchioli several generation of Respiratory bronchioli (= 3 generations) proceed. From them follow several generations of Alveolar ducts (= 3 generations) that in Alveolar sacculi (last generation = 23rd generation) end Fig. 12 - Overview of prenatal lung development

Histological image of an alveolar duct.

More info For the branching out of ever new lung buds an interaction between the respiratory endodermal epithelium and the surrounding pulmonary mesenchyma is primarily responsible. Mainly the epidermal growth factor (EGF) and the extracellular form of the transforming growth factors (TGF-) appear to be important for lung development. In addition, one finds specific extracellular matrix components like collagen of types I and III, as well as proteoglycan and the fibronectin and syndecan glycoproteins. These molecules are found around the

passages and in the forks of the bronchial tree. They are responsible for the stabilization of the already formed structures - these are not present in the regions of the newly formed branches. Epimorphine, a further protein, appears to promote the formation of epithelial passages. If epimorphine is blocked by antibodies, the epithelium that lies above it can not form itself into tubes and remains unorganized. (5)