16 Lung Development Flashcards
Q: What is the function of the lung? what else is needed? What can a better understanding in lung development lead to?
A: Function of lung is to produce a large gas exchange area [100m2] in a relatively small volume
-good pulmonary vasculature
may help treat and repair damaged lungs in later life (and diagnostics)
Q: What can affect lung growth? (3) What effect can abnormalities have?
What determines normal lung development?
A: Conditions of conception, in utero and in infancy affect lung growth and abnormalities may have life long impact
Crucial interaction between the airways and pulmonary vessels throughout development (send chemical messengers to and from structures)
Q: Timeline for lung development. Explain 5 stages- time and what grows.
What’s happening along side this growth?
A: 4 stages in utero
Embryonic phase – 0-7 weeks
lung buds (pushing out into mesenchymal tissue)
main bronchi (trachea branching into them)
Pseudoglandular – 5-17 weeks
conducting airways
bronchi & bronchioli (ongoing branching/ bifurcations)
Canalicular – 16-27 weeks
respiratory airways (laying down of)
blood gas barrier (basic components start developing)
Saccular/Alveolar -28-40 weeks
Alveoli appear
stage where infants become viable
Postnatal – adolescence
Alveoli multiply and enlarge in size with chest cavity (Alveoli appear before birth and continue to grow in early childhood)
blood vessel development
Q: 3 stages of blood vessel development (of lungs). Include what stage of lung development they coincide with.
A: Vasculogenesis // Branching morphogenesis
- occur along the skeleton that airway creates
- during embryonic and pseudoglandular phase (1 and 2)
Blood gas barrier
- during canalicular phase (phase 3)
Alveologenesis (formation of new alveoli) and angiogenesis (new blood vessels form from old ones)
- during saccular/adolescence phase (phase 4)
Q: Branching during embryogenesis. (3)
A: determines lobes-> can see branching buds growing into mesenchymal tissue
begins as asymmetric
can see by 56 days 3 lobes of right and 2 of left
Q: When does the pseudoglandular phase occur? Main process occurring? What is present by the end of it? What continues to develop? (3) in what phase?
A: 2nd phase, 5-17 weeks
Branching morphogenesis of airways into mesenchyme
Pre-acinar airways (conducting airways, not part of gas exchange) all present by 17 weeks
Development of cartilage, gland and smooth muscle tissue – continues into canalicular phase
Q: What determines branching morphogenesis? 3 examples. Describe the involvement of 2 cells.
What pattern does branching occur in humans?
A: Communication between epithelial cells in distal branching lung buds and surrounding mesenchyme (Epithelial-mesenchymal interaction) eg growth factors, cytokines and receptors
- Epithelial cells at tips of buds are highly proliferative multipotent progenitor cells
- Cells behind the tip divide and differentiate into the various cell types
bifurcation pattern
Q: What factors are involved in early lung bud formation? (2) Later?
A: Genetic and Transcription factors [TTF-1]
Later a variety of growth factors are important
Q: Name 4 growth factors in lung development. Include role. Balance?
A: Inductive/stimulating
FGF- branching morphogenesis, subtypes found in epithelium and mesenchyme
EGF - epithelial proliferation and differentiation
Inhibitory
TGFb - matrix synthesis, surfactant production, inhibits proliferation of epithelium and blood vessels
Retinoic acid - inhibits branching
without inhib you get overgrowth/malignancies
Q: Describe the process of endothelial differentiation. Where? (2) what makes them visible? What can happen to some? process? What stimulates endothelial differentiation?
End result?
A: (blood vessels)
CD31 (brown) demonstrates endothelial cells -> see them growing around lung bud-> along skeleton created by branching airways (act as structural template)
These differentiate in the mesenchyme around the lung bud
They coalesce to form capillaries – a process known as vasculogenesis
VEGF produced by epithelial cells (at tip of lung bud)
get pulmonary vasculature-> where blood vessels grow around alveoli = capillary beds -> where most gas exchange occurs
Q: When does the canalicular phase occur? What occurs? (4)
A: 16-27 weeks
- The airspaces at the periphery enlarge
- Thinning of epithelium by underlying capillaries allows gas exchange (Blood gas barrier)
- Epithelial differentiation into Type I and II cells (I produces surfactant)
- Surfactant first detectable at 24-25 wks (TGFb)
Q: Role of surfactant?
A: prevent airways sticking together with you breathe out
Q: Describe the 3 stage formation of the alveolar walls. Draw associated image. When does this occur? How does the interstitium change?
A: 1. Saccule wall, epithelium on both sides with double capillary network. Myofibroblast (produces elastin) and elastin fibres at intervals along wall (interstitium quite thick)
- Secondary septa develop from wall led by elastin produced by myofibroblast. Capillary lines both sides with matrix between
- Capillaries have coalesced to form one sheet alveolar wall, thinner and longer with less matrix. Muscle and elastin still at tip (thinned interstitium)
last 10 weeks (saccular/alveolar phase)
Q: How does the number of alveoli change as we grow? Diagram.
A: REFER
at 40 weeks when we’re born= 150 million -> 1/3 of the amount we are to have in adulthood
continues until late adolescence or early adulthood
Q: Infants born at term. Describe the lungs. What is present? (4)
A: small lung volume and related to body weight
- All airways present and differentiated (cartilage, glands, muscle, nerves)
- 33-50% alveoli allow normal gas exchange
- Blood gas barrier as in adult
- Most arteries and veins (pulmonary vascular system) present
Q: Changes at birth in blood vessels. Pulmonary vascular resistance? Pulmonary blood flow? Arterial lumen and wall?
What happens after arterial wall changes? Result? (2)
A: Decrease in pulmonary vascular resistance (at point of delivery)
10 fold rise in pulmonary blood flow
Arterial lumen increases and wall thins rapidly via change in cell shape and cytoskeletal organisation not loss of cells
Once thinning has occurred, arteries grow and maintain a relatively thin wall
Low pressure, low resistance pulmonary vascular system (very different to systemic)
Q: 4 possible mechanisms to increase flow after birth? What is the increase?
A: 10 fold rise in pulmonary blood flow
Expansion of alveoli dilates arteries - direct physical effect
Expansion stimulates release of vasodilator agents (NO, PGI2)
Inhibition of vasoconstrictors present during fetal life (ET)
Direct effect of oxygen on smooth muscle cells (causing relaxation and vasodilation that’s needed)
Q: Child and adolescence airway growth. How does lung volume change? Max? Growth type? (2) What else increases?
A: Lung volume increases x30,
Maximum lung volume at 22years in males
Airways increase in length and width x 2-3 by symmetrical growth
Dysanaptic growth during the early period - alveoli growing more than airways (airways relatively large in infants)
Structural elements of the wall increase
Q: Child and adolescence growth of alveoli. How does alveoli number change? Adult? Changes until? What else changes along side?
A: Alveoli increase in number up to 2-3 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)
Q: Summarise the landmarks in lung development. (5)
A: 6 weeks- lobar airways
16 weeks- pre acinar airway complete
30 weeks-respiratory airways present and alveoli first appear
newborn- 1/3-1/2 adult alveoli number present
3 years old- most alveoli present
Q: Not everyone has normal ciliary beat function. Condition? Impact?
A: Primary Ciliary Dyskinesia = genetic mutation
big impact on mucous clearance from lungs
normal arrangement= 9+2 -> with dynein arms = in this condition both inner and outer are gone -> cilia are static
Q: Describe bronchial cartilage. What can happen to them? (4)
A: Incomplete rings posteriorly / Irregular plates
complete rings are bad-> can cause extreme resp distress -> needs reconstruction
Calcify with age
Can be malacic= abnormal softening of a tissue:
Generalised – laryngotracheomalacia
Localised – malacic segment
Q: What is Laryngomalacia?
A: softening of larynx to give omega shaped epiglottis and aryepiglottic folds that can fold into airway = block
Q: 3 lung growth abnormalities.
A: Agenesis – complete absence of lung and vessel (rare-> all body content shifts-> could be caused by lack of blood flow during development)
Aplasia – blind ending bronchus, no lung or vessel
Hypolasia – bronchus and rudimentary lung are present, all elements are reduced in size and number (relatively common -> secondary to lack of space)
Q: What can cause hypoplasia of lung? (5)
A: 1. Lack of space
Intrathoracic or extrathoracic
Hernia (L = 75 – 90%)
Chest wall pathology
Oligohydramnios (less amniotic fluid)
Lymphatic or cardiac mass
- lack of growth
Congenital Thoracic malformation (lots of conditions- CPAM, CPAM II, CLHL, Intralobar Sequestration)
Q: What is CPAM? Diagnosis? Pathogenesis? (2)
A: Congenital Thoracic malformation
Cystic Pulmonary Airway Malformation
Mostly diagnosed on antenatal US
Pathogenesis:
- Defect in pulmonary mesenchyma, abnormal differentiation 5-7th week
- Normal blood supply
Q: Type II CPAM. Describe. Associated with? Histology shows?
A: Congenital Thoracic malformation
Multiple small cysts
May be associated with other congenital defects- renal agenesis, cardiovascular defects, diaphragmatic hernia and syryngomyelia
Histologically bronchiolar epithelium with overgrowth, separated by alveolar tissue which was underdeveloped
Q: What is CLHL? Describe. Underlying cause? (4) Common in? (2) Association with?
A: Congenital Thoracic malformation
(Congenital Lobar Emphysema) Congenital Large Hyperlucent Lobe (CLHL)
Progressive lobar overexpansion
- Weak cartilage
- Extrinsic compression
- One way valve effect
- Alveoli expand (not disrupted)
Left Upper Lobe > RML >RUL
Males > females
CHD association
Q: Intralobar Sequestration. What is it? (2) Predominance? Cause? (2) Treatment?
A: Congenital Thoracic malformation
- Abnormal segment share visceral pleural covering of normal lung
- No communication to tracheobronchial tree but abnormal blood supply
Lower lobe predominance, L > R
Due to chronic bronchial obstruction and chronic post-obstructive pneumonia
treat by occluding abnormal blood vessel
Q: Scimitar syndrome. Classic SS includes? (4)
A: - Anomalous pulmonary venous drainage of the right lung to the IVC , usually close to the junction of the right atrium
- Associated right lung and right pulmonary artery hypoplasia
- Dextrocardia where heart points to right side of heart instead
- Anomalous systemic arterial supply.
