Lung development

Question 1

How do pulmonary blood vessels develop?

Answer 1

In parallel with airways - close interaction
Forms around framework of budding airways
Blood gas barrier formed in canalicular phase

Sustained addition of newly formed endothelial tubes at the lung periphery as each airway division occurs
As the capillaries add on at the periphery the arteries and veins get longer

Question 2

What occurs during the embryonic phase?

Answer 2

Asymmetric branching occurs to produce 3 lobes on the right and 2 on the left

Question 3

When is the pseudoglandular phase?

Answer 3

5-17 weeks

Question 4

What occurs during the pesudoglandular phase?

Answer 4

• Branching morphogenesis of airways into mesenchyme
• Pre-acinar airways all present by 17 weeks
• Development of cartilage, gland and smooth muscle tissue – continues into canalicular phase.

Question 5

What factors drive branching morphogenesis in the pesudeoglandular?

Answer 5

• Lung buds - consistent appearance during airway formation (5-17 wks in man)

• Epithelial cells at tips of buds are highly proliferative multipotent progenitor cells
• Cells behind the tip divide and differentiate into the various cell types
• Sustained addition of newly formed endothelial tubes at the lung periphery as each airway division occurs
• As the capillaries add on at the periphery the arteries and veins get longer

• Communication between epithelial cells in distal branching lung buds and surrounding mesenchyme
- Affected by inductive and inhibitory signals

Question 6

What are the inductive growth factors in lung development?

Answer 6

• FGF- branching morphogenesis, subtypes found in epithelium and mesenchyme
• EGF - epithelial proliferation and differentiation

Question 7

What are the inhibitory growth factors in lung development?

Answer 7

• TGFb - matrix synthesis, surfactant production, inhibits proliferation of epithelium and blood vessels
• Retinoic acid - inhibits branching

Question 8

How does endothelial differentiation occur in the lung?

Answer 8

1. differentiate in the mesenchyme around the lung bud
2. coalesce to form capillaries – vasculogenesis
   - Airways act as structural template (create physical stimulus)
   - VEGF produced by epithelial cells at tip stimulates endothelial differentiation (form matrix/lattice allowing gas exchange)

Question 9

When is the canalicular stage?

Answer 9

16-27 weeks

Question 10

What occurs during the canalicular stage?

Answer 10

• Airspaces at the periphery enlarge and start to form
• Thinning of epithelium around underlying capillaries allows gas exchange
• Blood gas barrier required in post-natal life
• Epithelial differentiation into Type I and II cells

Question 11

When is surfactant first detectable?

Answer 11

• 24-25 wks

Question 12

When is the saccular/alveolar stage?

Answer 12

28-40

Question 13

What occurs during the saccular/alveolar stage?

Answer 13

1. Alveolar walls form first as saccule walls with double capillary networks
2. Form secondary septa
3. Form alveolar walls as the capillaries coalesce to form one sheet, with elastin in the wall produce by myofibroblasts

Question 14

What is the structure of the lung at birth?

Answer 14

• Volume small and related to body weight
• All airways present and differentiated (cartilage, glands, muscle, nerves)
• Blood gas barrier as in adult
• 33-50% alveoli allow normal gas exchange
• Most arteries and veins present

Question 15

What are the pulmonary- vascular changes in blood vessels at birth?

Answer 15

• Expansion of arteries dilate arteries to increase blood flow
• Expansion stimulates release of vasodilators such as NO/PGI2
• Vasoconstrictors present during foetal life - if not inhibited then will get pulmonary hypertension
• Direct effect of oxygen on smooth muscle cells

Question 16

What are the alveolar changes in childhood and adolescence?

Answer 16

• Alveoli increase in number up to 9-13 years
• Adult alveolar number (300-600 million)
• Alveoli increase in size and complexity to increase surface area until body growth complete after adolescence(x20)
• Arteries, veins and capillaries increase alongside the alveoli (cap volume x35)

Question 17

What are the types of lung growth abnormalities?

Answer 17

• Agenesis – complete absence of lung and vessel (rare)
  
  • Commonly associated with other pathology

• Aplasia – blind ending bronchus, no lung or vessel

• Hypolasia – bronchus and rudimentary lung are present, all elements are reduced in size and number (underdevelopment)
• Relatively common and usually secondary
• May be intra or extrathoracic
• May be caused by hernia, chest wall pathology,
oligohydramnios, lymphatic or cardiac mass

Question 18

What factors interfere with normal lung development and affect susceptibility to lung disease?

Answer 18

Undernutrition
preterm birth
reduced intrathoracic space
respiratory infections
maternal tobacco smoking
exposure to allergens

Question 19

What are specific examples of lung defects?

Answer 19

Primary ciliary dyskinesia: AR mutation (45 known) that impacts on ciliary function; dynein arms are absent, causing cilia to become static so mucous is not moved and cleared; will get bronchiectasis and respiratory failure

Congenital bronchial cartilage defects: normally incomplete rings with irregular plates, but can be malacic (floppy) in generalised or localised (occur due to other developmental issue) fashion - always check CVD status

Laryngomalacia: omega shaped epiglottis with folds that collapse on inspiration - severe airway obstruction

Cystic Pulmonary Airway Malformation (CPAM/CCAM): 1:8,000-1:35,000 mostly diagnosed on antenatal ultrasound; lethal don’t survive but usually seen well; normal blood supply with defect in pulmonary mesenchyma causing abnormal differentiation in early weeks

Congenital lobar emphysema: progressive lobar overexpansion, expanding over midline and squashing other lobes due to weak cartilage or one way valve effects - association with CHD

Intralobal sequestration: lower lobes usually affected and have aberrant blood supply that do not ventilate - no communication to tracheobronchial tree