17. Lung development

Question 1

Describe the timeline of lung development

Answer 1

Embryonic phase (0-7 weeks): Lung buds and Main bronchi
Pseudoglandular (5-17 weeks): Conducting airways, Bronchi and bronchioli
Canalicular (16-27 weeks): Respiratory airways and Blood gas barrier
Saccular/Alveolar (28-40 weeks): Alveoli appear

Question 2

How does blood vessel development in the airways occur?

Answer 2

In parallel with airway development

Lots of interaction between blood vessels and airways in lung development, very dependent on each other

Question 3

Describe the timeline of blood vessel development in the lung

Answer 3

Vasculogenesis
Branching morphogenesis
Blood gas barrier
Alveo- and angiogenesis

Question 4

Describe organogenesis in the lungs

Answer 4

Asymmetric
Right lung: 3 lobes
Left lung: 2 lobes

Question 5

Describe Pseudoglandular phase (5-17 weeks)

Answer 5

Branching morphogenesis of airways into mesenchyme
Pre-acinar airways all present by 17 weeks
Beginning of development of cartilage, gland and smooth muscle tissue

Question 6

What factors drive branching morphogenesis?

Answer 6

Lung buds: consistent appearance during airway formation (5-17 weeks 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
Communication between epithelial cells in distal branching lung buds and surrounding mesenchyme

Question 7

Describe the inductive (stimulatory) factors in lung development

Answer 7

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

Question 8

Describe the inhibitory factors in lung development

Answer 8

TGF-Beta: matrix synthesis, surfactant production, inhibits proliferation of epithelium and blood vessels
Retinoic acid: inhibits branching

Question 9

Describe the effects of Vascular EGF released from the tip of the lung bud on endothelial cells

Answer 9

Endothelial cells differentiate and coalesce to form capillaries
Airways act as a structural template:
create a physical stimulus by growing into mesenchyme, stimulates production of growth factors required for neighbouring cells to differentiate

Question 10

What is branching morphogenesis matched by?

Answer 10

Vasculogenesis

Question 11

Describe the canalicular stage (16-27 weeks)

Answer 11

Airspaces at the periphery enlarge
Thinning of epithelium around underlying capillaries allows gas exchange (prep. blood gas barrier)
Epithelial differentiation into Type I (thin out) and Type II cells (produce surfactant)
Surfactant 1st detectable at 24-25 weeks: reduces surface tension, allows airspaces to stay open even when airways collapse down

Question 12

Describe the mechanism of formation of alveolar walls

Answer 12

Saccule wall, epithelium on both sides with double capillary network. Little bumps in which Myofibroblast produces elastin fibres at intervals along wall .
Secondary septa develop from wall, led by elastin produced by myofibroblast. Capillary lines both sides with matrix between.
Alveolus
Capillaries have coalesced to form 1 sheet alveolar wall, thinner and longer with less matrix. Muscle and elastin still at tip

Question 13

Describe the Saccular/Alveolar stage (28 – 40 weeks)

Answer 13

Alveoli appear
Multiply up to 9-12 years of age
~ 1/2 adult number by term (100-150 million)

Question 14

Describe the lung at birth in man

Answer 14

Volume small and related to body weight
All airways present and differentiated
Same blood gas barrier as in adult (smaller and less developed, but has same function)
Have 33-50% alveoli that they will have when they’re fully grown (still allow normal gas exchange)
Most arteries and veins present

Question 15

3 mechanisms to increase flow after birth

Answer 15

Take 1st breath
Change in blood pressure
Growth of alveoli through childhood

Question 16

What happens when a baby takes its 1st breath?

Answer 16

Expansion of alveoli dilates arteries: direct physical effect
Expansion stimulates release of vasodilator agents (NO, PGI2)
Inhibition of vasoconstrictors present during foetal life (ET)
Direct effect of oxygen on smooth muscle cells

Question 17

How does blood pressure change at birth?

Answer 17

Decrease in pulmonary vascular resistance
10 fold rise in pulmonary blood flow
Arterial lumen increases and wall thins rapidly
Once thinning has occurred, arteries grow and maintain a relatively thin wall
We want a: low pressure, low resistance pulmonary vascular system

Question 18

Growth of alveoli through childhood

Answer 18

Alveoli increase in number up to adolescence (Adult 300-600 million)
Alveoli increase in size and complexity to increase SA until body growth complete after adolescence
Arteries, veins and capillaries increase alongside the alveoli

Question 19

Describe the epithelium of the airways

Answer 19

Columnar epithelium
Goblet cells produce mucins (mucous secreted onto surface)
Ciliated surface: wafts mucous (primary defence)

Question 20

Primary ciliary dyskinesia

Answer 20

Impact on ciliary function e.g. Outer/ Inner dynein arm defect
No muco-ciliary clearance, mucous accumulates
Chronic suctive lung disease

Question 21

Describe the structure of cilia

Answer 21

Highly conserved structure
9 + 2 formation
Microtubule doublet pairs
All have hooks (Dynein arms) which affect sliding motion of 1 microtubular pair against the other

Question 22

Congenital bronchial cartilage defects:

What causes generalised malacia (floppiness)?

Answer 22

Slow development

Laryngotracheomalcia

Question 23

Congenital bronchial cartilage defects:

What causes localised malacia (floppiness)?

Answer 23

Malacic segment often occur due to some other developmental issue e.g. abnormal blood vessels around heart
Causes external compression of airways, so cartilage rings don’t develop normally

Question 24

What can go wrong with cartilage development?

Answer 24

Cartilage may form complete ring instead of horseshoe (narrowing of airway)
Laryngomalacia: omega shaped epiglottis, can collapse in on inhalation= airway obstruction

Question 25

List 3 lung growth anomalies

Answer 25

Agenesis: complete absence of lung and vessel
Aplasia: blind ending bronchus, no lung or vessel
Hypoplasia: bronchus and rudimentary lung are present, all elements are reduced in size and number

Question 26

Describe lung Agenesis

Answer 26

Rare
Usually results from abnormal flow in 4th week
Commonly associated with other pathology
Mediastinal shift towards an opaque hemithorax

Question 27

What may cause lung hypoplasia due to lack of space? (Intrathoracic or extra-thoracic causes)

Answer 27

Diaphragmatic hernia
Chest wall pathology e.g. Asphyxiating thoracic dystrophy- lungs can’t grow as ribcage so small
Oligohydramnios (lack of amniotic fluid around baby)
Lymphatic or cardiac mass

Question 28

What causes lung hypoplasia due to lack of growth?

Answer 28

Congenital Thoracic Malformation (CTM)

Question 29

Congenital Thoracic Malformation (CTM):

Cystic Pulmonary Airway Malformation (CCAM)

Answer 29

Defect in pulmonary mesenchyma, abnormal differentiation 5-7th week
Normal blood supply

Question 30

Congenital Thoracic Malformation (CTM):

Type 2 Cystic Pulmonary Airway Malformation (CCAM)

Answer 30

Multiple small cysts on imaging

May be associated with renal agenesis, cardiovascular defects and diaphragmatic hernia

Question 31

Congenital Thoracic Malformation (CTM):
Congenital Lobal Emphysema
(Congenital Large Hyperlucent Lobe (CLHL))

Answer 31

Progressive lobar over-expansion
Left Upper Lobe > Right Middle Lobe >Right Upper Lobe
Males > females
Associated with Congenital heart disease

Question 32

Congenital Thoracic Malformation (CTM):
Congenital Lobal Emphysema
(Congenital Large Hyperlucent Lobe (CLHL)) underlying cause

Answer 32

Weak cartilage
Extrinsic compression
Slit like- One way valve effect
Alveoli expand

Question 33

Congenital Thoracic Malformation (CTM):

Intralobar Sequestration

Answer 33

Abnormal segment share visceral pleural covering of normal lung
No communication to tracheobronchial tree
Not necessarily lung tissue, has aberrant blood supply
Not ventilating, but does have blood supply
Can get infected