Fetal Lung Development and Lung Adaptations at Birth

Question 1

Give a basic overview of the characteristics of fetal vs newborn/adult lungs:

Answer 1

Fetal lungs:

• Not functional for gaseous exchange
• Filled with fluid
• Receive only 5-10% of blood from right hand side of heart
• Highly expanded

Newborn/Adult:

• Gas exchange organ
• Air-filled
• Recieve 100% of blood from right heart
• Less expanded

Question 2

What features must be present in the lungs for efficient gas exchange to take place at birth?

Answer 2

. Large surface area for gas exchange

• Large area of blood
• Mature differentiated AECs (type 1 and type 2)
• Surfactant must be present to decrease surface tension and prevent lung collapse
• Lung tissue must be compliant (expands easily)
• Lung must be capable of clearing lung liquid
• Pulmonary vascular resistance must be able to decrease to facilitate the increase in pulmonary blood flow

Question 3

What are the 5 stages of lung development:

Answer 3

1. Embryonic: 3-7 weeks
   - Lung bud arises from ventral foregut endoderm
   - primary to tertiary bronchi form
2. Pseudoglandular: 5-17 weeks
   - Respiratory bronchioles and acinar tubules form
   - trachobronchial tree complete by 17 weeks
   - lymphatics, arteries, veins and autonomic innveration arise
3. Cannciular: 16-26 weeks
   - Acinar tubules lengthen, subdivide and widen
   - mesenchyme thins
   - type 1 and 2 AECs differentiate
   - surfactant is synthesised and stored
   - fetal lung liquid increased
   - gas exchange first possible late cannalicular stage -23 weeks (limit of viability)
   - FBMs initiated
4. Saccular: 24-38 weeks
   - Acinar tubules expand to form fluid filled acs
   - alveolar septal walls form
   - type 1 AECs flatten and elongate
   - surfactant secreted by type 2 AECs
5. Alevolar: 36 weeks- 2 years
   - Secondary alveolar septa divide saccules into true alveoli
   - alveolar SA avaliable for gas exchange increases

Question 4

What factors control lung development?

Answer 4

1. Local factors:
   - genes
   - proteins
   - miRNA
   - epigenetics
   e. g. PDGF, glucocorticoid receptors, FGFs
2. Circulating factors:
   - Glucocorcitoids (cortisol)
   - Increase in levels in later gestation
   - Promote thinning of mesenchymal tissue, increase in surfactant production, lung compliance, alveolarisation and matures mechanism for lung liquid reabsorption
3. Physical factors:
   - Lung expansion
   - Lung liquid is actively secreted by epithelial cells
   - Level of lung liquid and expansion controlled by lung liquid secretion and fetal breathing movements
   - Critical for lung cell growth and proliferation and alveolar development
   - More expansion favours type 1 AEC differentiation

Question 5

How is lung liquid formed?

Answer 5

1. The Na/K ATPase pump on the basalolateral surface of the lung epithelial cells actively pumps 3Na+ into the interstitial tissue and 2K+ into the cell
2. This creates an electrochemical gradient that favours the movement of Na+ back into the cell
3. Na+ re-enters the cell via Na/K/Cl transporter on the basolateral surface
4. The movement of Na+ with Cl- results in an accumulation of Cl- within the cell
5. Cl- then leaves the cell via Cl- channels on the apical surface and increases the ionic concentration in the lung lumen
6. This establishes an ionic gradient that favours the movement of water into the lung lumen which forms lung liquid

Question 6

What is lung hypoplasia?

Answer 6

• Lung hypoplasia is when the lungs fail to grow and develop adequates resulting in small in immature lung
• There are 4 main causes, all of which relate to lack of fetal lung expansion:
  1. Oligohydramnios
  2. Congenital diaphragmatic hernia
  3. Pleural effusions
  4. Musculoskeletal conditions affecting ribcage and diaphragm

Question 7

What therapies are used to manage the effect of preterm birth on the lungs?

Answer 7

1. Antenatal corticosteroid therapy: very successful therapeutic as it triggers the maturation of the lungs and production of surfactant, may have deletrious effects on other aspects of fetal development however
2. Research aims to indentify downstream genes and proteins activated by glucocorticoids to generate a more targeted treatment
3. New experiment involving delivering preterm lambs into artificial uteruses can help delay the cardiorespiratory transition of preterm infants by up to a a week thus allowing more time for the fetal lungs to mature

Question 8

What are the 3 mechanisms for clearing lung liquid and allowing lung aeration at birth?

Answer 8

1. Postural changes
   - Primarily occurs after fetal membranes have ruptured and the amniotic fluid is lost
   - Increase in pressure by uterus causes spinal flexion
   - Increases hydrostatic pressure in chest cavity which forces more lung liquid out via the mouth
2. Active lung liquid reabsorption:
   - Reversal of osmotic gradient establishing lung liquid secretion
3. 1. During stress of labour there is an increase in adrenaline
4. 2. Adrenaline binds to beta-adrenoreceptors on lung epithelial cells and results in an increase in cAMP in the cells
5. 3. Increase in cAMP opens sodium channels on the apical surface of the cells causing an influx of sodium from the lung lumen into the cell cytosol
6. 4. An increase in intracellular sodium causes the Na/K ATPase pump on the basolateral surface to pump out 3Na+ ions per every 2 K+ ions
7. 5. This results in there being a higher ionic concentration in the interstitial fluid which causes the osmotic movement of water from the lung lumen back into the lung interstitial tissue
8. Pressure created by large inspiratory efforts
   - After birth when the baby makes large inspiratory efforts (or is ventilated) the movement of air into the airways creates a much higher pressure in the airway lumen than in the lung tissue, generating a transpulmonary pressure gradient
   - With each large inspiratory effort the transpulmonary pressure gradient is established and more lung liquid is forced into the interstitial tissue
   - This allows the very rapid movement of fluid from the airways into the lung tissue which is then drained by the lymphatics and blood vessels

Question 9

How does the respiratory transition at birth affect lung development?

Answer 9

• After birth the lung liquid is forced out of the airways and replaced with air which reduces lung expansion
• Additionally the surface tension created by the lung liquid interfaced (although decreased by surfactant) also promotes the collapse of the lungs
• The loss of lung expansion when aeration occurs results in a decrease in the rate of lung cell proliferation and growth
• The decrease in expansion also favours the differentiation of type 1 AECs
• The rate of alveoli differentiation also decreases

Question 10

Describe situations which may impair the respiratory transition at birth and explain why:

Answer 10

1. Prematurity: preterm babies have underdeveloped airways, alveoli and overall lung structure, lung liquid reabsorption is impaired, there is reduced lung compliance, lack of surfactant, impaired gaseous exchange and they are less able to undergo large inspiratory efforts
2. Non-Labour C-section delivery: the fetus does not undergo the first 2 mechanisms for the clearance of lung liquid prior to birth, as the fetus does not undergo compression by the uterus during contractions after rupture of the membranes and may not have the increase in adrenaline due to labour driving lung liquid reabsorption
3. Oligohydramnios: increases the pressure on abdomen and chest so there is a prolonged reduction in lung expansion which slows lung growth and maturation so infants may have lung hypoplasia
4. Congenital Diaphragmatic Hernia: the abdominal contents move up into chest cavity and compress the lungs and result in a prolonged reduction in lung expansion and potentially severe lung hypoplasia

Question 11

What is respiratory distress syndrome?

Answer 11

• Also known as hyaline membrane disease
• Caused by insufficient surfactant in the lung (usually due to premature birth)
• Treatment is antenatal corticosteroids to avoid, or exogenous surfactant

Question 12

What is bronchopulmonary dysplasia?

Answer 12

• Prolonged requirement for respiratory support (after 36 weeks corrected gestational age)
• Pathologically defined as abnormal lung development, there is cessation of alveolarisation, capillary dyplasia, thick interstitial tissue, inflammation and poor capacity for gas exchange
• Primarily a disease or prematurity (caused by lung immaturity)