Embryology of the Lungs

Question 1

During what week does the respiratory diverticulum appear?

Answer 1

• the respiratory diverticulum appears as an outpouching from the ventral wall of the foregut during week 4

Question 2

What substance and transcription factor are important in determining the location and appearance of the lung bud (respiratory diverticulum)?

Answer 2

• appearance and location of the lung bud are dependent on an increase in retinoic acid produced by adjacent mesoderm
• an increase in RA upregulates TBX4 expressed in the endoderm of the gut tube at the site of the lung bud
• TBX4 induces formation of the lung bud and continued growth and differentiation of the lungs

Question 3

From which germ cell layer are the lungs developed from?

Answer 3

• the epithelial lining of the larynx, trachea, bronchi and lungs is of endodermal origin
• the cartilagenous, muscular and connective tissue components of the trachea and lungs are derived from splanchnic mesoderm surrounding the foregut

Question 4

On what day does the lung bud appear?

How does it grow and what separates it from the foregut?

Answer 4

• it appears on day 22 and is initially in open communication with the foregut
• as it grows ventrocaudally, 2 longitudinal tracheo-oesophageal ridges form to separate the respiratory diverticulum from the foregut
• the lung bud remains in communication with the laryngeal inlet

Question 5

What happens to the tracheosophageal ridges after they have formed?

Answer 5

• the tracheoesophageal ridges fuse to form the tracheoesophageal septum
• this divides the foregut into a dorsal portion (oesophagus) and ventral portion (trachea and lung buds)
• the respiratory diverticulum then divides to form 2 lung buds

Question 6

What is a tracheosophageal fistula and why does it occur?

Answer 6

• TOFs result from incomplete division of the foregut into oesophageal and respiratory portions
• abnormalities in partitioning of the oesophagus and trachea by the tracheoesophageal septum results in oesophageal atresia +/- TOFs
• a fistula describes an abnormal connection

Question 7

What are TOFs associated with in 90% of cases?

Answer 7

closed or absent oesophageal atresia

• the upper portion of the oesophagus ends in a blind pouch
• the lower segment of the oesophagus forms a fistula with the trachea

Question 8

What 2 variations of TOFs each account for 4% of cases?

Answer 8

• isolated oesophageal atresia where there is no formation of a fistula
• H-type TOF without oesophageal atresia

Question 9

What is the most common complication of TOF with oesophageal atresia?

Answer 9

• the upper oesophagus ends rapidly and lower oesophagus forms a fistula with the trachea
• the abdomen rapidly distends as the stomach fills with air
• it can also cause aspiration pneumonia as milk can enter the trachea from the blind-ended sac

Question 10

What is the clinical consequence of a H-type TOF?

Answer 10

• this can lead to milk being “driven” into the respiratory system

Question 11

What other congenital abnormalities are TOFs usually associated with?

Answer 11

• they are most commonly associated with cardiac defects (1/3 of cases)
• they are part of the VACTERL association - a collection of defects with unknown causation but occur more frequently than predicted by chance alone

Question 12

What is the first stage in formation of the lungs?

What happens during week 5 of development?

Answer 12

• during partitioning of the oesophagus and the lung bud, right and left bronchial buds form
• further growth and differentiation at the start of week 5 leads to enlargement of the bronchial buds to form right and left main bronchi
• the right main bronchus forms 3 secondary bronchi
• the left main bronchus forms 2 secondary bronchi

Question 13

How do the secondary bronchi further divide during week 6 of development?

Answer 13

• further branching results in the formation of tertiary bronchi, which will each supply a bronchopulmonary segment
• there are 10 tertiary bronchi on the right and 8 on the left

Question 14

Following the formation of tertiary bronchi, what further divisions occur?

How is this branching regulated?

Answer 14

• branching continues to form terminal bronchioles by week 16 and respiratory bronchioles by week 26
• the first alveoli develop in week 36
• branching is regulated in part by the interaction of the epithelium (derived from the foregut) with the overlying visceral mesoderm
• the visceral mesoderm forms the cartilage, smooth muscle, connective tissue and capillaries

Question 15

What forms the 2 different types of pleura?

Answer 15

• visceral mesoderm forms the visceral pleura
• parietal mesoderm forms the parietal pleura

Question 16

What is pulmonary agenesis and why does it occur?

Answer 16

• it occurs when the lung bud fails to split, leading to complete absence of bronchi and vasculature
• it can be unilateral or bilateral
• bilateral pulmonary agenesis is incompatible with life

Question 17

What is the typical clinical presentation of unilateral pulmonary agenesis?

Answer 17

• child usually develops respiratory distress if the remaining lung is compromised (usually by LRTI)
• 60% have other congenital abnormalities including:
  
  • diaphragmatic hernias
  • cardiac lesions
  • skeletal abnormalities
• agenesis of the right lung is associated with a higher frequency of anomalies

Question 18

Why can the presentation of pulmonary agenesis be variable?

Answer 18

• the severity depends on the area of tissue affected - a single lobe or a whole lung?
• clinical features vary from asymptomatic to respiratory complaints such as:
  • dyspnoea
  • recurrent pulmonary infections
  • respiratory distress
  • limited exercise tolerance

Question 19

How would an X-ray and endoscopic view confirm pulmonary agenesis?

Answer 19

• there would be enlargement of the lung that is present and deviation of the heart and trachea on X-ray
• the bronchus of the affected side would be absent on endoscopic view

Question 20

What is pulmonary hypoplasia?

What is it often associated with?

Answer 20

• this occurs when all the components of the lung are present, but incompletely developed
• the severity of hypoplasia determines the degree of respiratory compromise
• there is an abnormally low number or size of bronchopulmonary segments or alveoli
• it is often found in association with a congenital diaphragmatic hernia (CDH)

Question 22

How can maturation of the lungs be divided into 4 periods?

Answer 22

1. pseudoglandular
2. canalicular
3. saccular / terminal sac
4. alveolar

Question 23

When does the pseudoglandular period take place?

What happens during this period?

Answer 23

• occurs between weeks 5-17
• branching of the respiratory tree occurs to form terminal bronchioles
• this begins as the bronchial tree develops as solid tubes, which bud to form bronchi, bronchioles and terminal bronchioles

Question 24

Could a foetus born during the pseudoglandular period survive?

Answer 24

• No, a foetus could not survive as respiration is not possible at this stage
• no respiratory bronchioles or alveoli are present during this period

Question 25

When does the canalicular phase take place?

What are the major changes that happen to the developing lungs during this period?

Answer 25

• the canalicular phase occurs between weeks 16-25
• the terminal bronchioles divide to form respiratory bronchioles
• each respiratory bronchiole divides into 3-6 alveolar ducts
• the ducts end in terminal sacs (primitive alveoli) that are surrounded by flat alveolar cells in close contact with neighbouring capillaries

Question 26

What happens to the vascular supply during the canalicular period?

Would a foetus born during this period be able to survive?

Answer 26

• mesodermal tissue becomes highly vascularised during this period
• respiration is possible towards the end of the canalicular period as sufficient numbers of terminal sacs have developed at the end of respiratory bronchioeles
• there are also sufficient numbers of capillaries to allow for adequate gas exchange

Question 27

When does the terminal sac period take place?

What happens during this period?

Answer 27

• this occurs from week 26 - birth
• the number of terminal sacs (primitive alveoli) steadily increases
• type I alveolar epithelial cells lining the terminal sacs become thinner, allowing capillaries to protrude into the alveolar sacs
• intimate contact between epithelial and endothelial cells forms the blood-air barrier

Question 28

How does the epithelium change during the terminal sac period?

Answer 28

• it differentiates to give rise to type I and type II pneumocytes

Type I pneumocytes:

• these are the thinned cells that line the alveolar sacs
• gas exchange takes place across these cells

Type II pneumocytes:

• these produce surfactant, which is needed to lower surface tension at the air-alveolar interface
• reducing surface tension facilitates inflation

Question 29

Can a foetus born during the terminal sac period survive?

Answer 29

• a foetus born prematurely (24 weeks) can survive in intensive care but may suffer from respiratory distress syndrome
• mature alveoli are not present before birth

Question 30

When does the alveolar period take place?

What happens during this period?

Answer 30

• the alveolar period takes place between 36 weeks and 8 years
• development of the lungs after birth is mainly due to an increase in the number of respiratory bronchioles and alveoli
• 95% of mature alveoli do not develop until after birth

Question 31

When do foetal breathing movements start?

Why is this important?

Answer 31

• foetal breathing movements begin in utero to allow for removal of amniotic fluid
• these movements stimulate lung development and condition respiratory muscles

Question 32

What happens when respiration begins at birth?

Answer 32

• any remaining lung fluid is rapidly resorbed by blood / lymph capillaries
• when fluid is resorbed from alveolar sacs, a thin layer of surfactant remains deposited as a thin phospholipid coat on alveolar cell membranes
• when air enters the lungs at the first breath, surfactant prevents collapse of the alveoli during expiration and allows for respiration

Question 33

How does lung development influence survival of a premature infant?

Answer 33

• the state of development of the lungs is a prime factor in determining prognosis when a child is born prematurely
• if they are born after 26 weeks, chance of survival is good as surfactant is produced in sufficient quantities
  
  • this is during the terminal sac period
• if they are born prior to 26 weeks, the chance of survival is poor as insufficient quantities of surfactant have been produced

Question 34

What happens in infant respiratory distress syndrome (RDS) at birth?

How can this develop into a chronic condition?

Answer 34

• laboured breathing threatens the infant with immediate asphyxiation
• there is an increased rate of breathing
• mechanical ventilation is needed to support breathing
• damage to the alveolar lining leads to fluid and serum proteins leaking into the alveolus
• continued injury can lead to detachment of the alveolar lining
• chronic lung injury in preterm infants can cause bronchopulmonary dysplasia

Question 35

What happens in bronchopulmonary dysplasia?

Answer 35

• it is a chronic lung disease in which premature infants, usually those who were treated with supplemental oxygen, require long-term oxygen therapy
• the alveoli that are present tend not to be mature enough to function normally

Question 36

What are the treatments available for infant respiratory distress syndrome?

Answer 36

• glucocorticoid treatment accelerates foetal lung development and surfactant production
• surfactant therapy can be performed with natural or artificial surfactants

it is more effective when surfactant A and B proteins are used

Question 37

What is surfactant protein B deficiency disease?

What is the prognosis?

Answer 37

• this is an autosomal recessive condition
• it leads to lethal respiratory failure within the first year of life despire mechanical ventilation and surfactant therapy