S4: Cardiorespiratory Adaptation at Birth I

Question 1

Describe the different number of phases occurring at different stages of gestation for lung development

Answer 1

1. The first thing that occurs is the embryonic growth of the lung buds from the foregut and this divides into the right and left. This occurs very early on in embryonic life.
2. At about 6 weeks, the lung buds are starting to branch to form terminal bronchioles and by around 16/17 weeks this branching has been completed. This period is called the pseudoglandular phase.
3. After 16/17 weeks there is no more branching rather there is development of the branches and this is called the canalicular phase where each bronchiole divides into 2+ respiratory bronchioles this occurs from 17-26 weeks.
4. Then is the saccular phase and this is where the respiratory bronchioles start to divide into the alveolar ducts and sacs. Capillaries also form around these.
5. By term alveoli are more established and these further mature into childhood. The adult no. of alveoli isn’t reached until about 5 years of age.
6. Surfactant production (and volume) starts at around 25 weeks and increases up to and after delivery.

Question 2

What growth factors are required for simultaneous growth of vascular elements, the tubular airway elements and growth of different cells types of the lung?

Answer 2

• Forkhead transcription factors (FOXA1/2 (HNF 3B) for proliferation, branching, cell differentiation, regulation SH.
• Hepatocyte nuclear factor 3β required for the lung buds to develop off the foregut.
• Fibroblast growth factor-10, sonic hedgehog, bone morphogenetic protein (BMP4) are all required for the outgrowth for new end buds.
• Gli proteins are required for the branching of the lungs.
• Vascular endothelial growth factor (VEGF) for angiogenesis around the alveoli.

Question 3

Describe alveolar development

Answer 3

• At 24 weeks the saccules of the alveoli start to develop and under VEGF capillaries develop around each saccule. This is vital for gas exchange later on.
• At 32 weeks there starts to be shallow indentations start to occur in the alveoli.
• Most development of the alveoli actually occurs post term and this is mainly by growing in number and by around 4/5yrs of age adult numbers have been reached.
• The actual size of the alveoli do not change much from birth onwards.

Question 4

When do cells of the lung develop?

Answer 4

There are the pneumocytes of which there are type 1 and type 2 and they are present from 22 weeks. From 24 weeks lamellar bodies are present (type II pneumocytes).

Question 5

Why is it important to understand lung development for lung pathology?

Answer 5

Anything that impacts on developmental processes can cause problems with lung development and function. To understand the effect problems have it is important to be aware of the way the lung develops.

Question 6

Describe how time of onset of issue affects structural pathology associated with problems in development

Answer 6

Time of onset of problem will impact on the effect. Before 16 weeks if the problem occurs, the branching can be irreversibly affected and there can potentially be a permanent reduction in the number of alveoli. If the insult occurs after 16 weeks, the branching would have already taken place so it will be alveolar numbers and function that will be affected.

Question 7

Describe extrinsic restriction affects structural pathology associated with problems in development

Answer 7

There can be extrinsic restriction of the lung (things outside the lung that squash it preventing it from developing normally).

• Congenital diaphragmatic hernia (CDH) where there is a defect in the diaphragm where gut contents herniate up the thorax. Usually occurs on the left side and this pushes the thoracic contents to the contralateral side squashing both aspects of the lung.
• Effusions where there is fluid developing around the lung that tends to be bilateral. This is more of a problem later in gestation.
• Thoracic or vertebral abnormalities e,g. thoracic dystrophy.

Question 8

Describe intrinsic restriction affects structural pathology associated with problems in development

Answer 8

There can be something inside the lung causing it to not develop normally such as lung cysts (cystic adenomatoid malformation).

Question 9

Describe how malnutrition and lifestyle affects structural pathology associated with problems in development

Answer 9

• Malnutrition such as vitamin A deficiency can cause structural abnormalities of the developing lung and less alveolar development.
• Smoking also.

Question 10

Describe the lung liquid in development

Answer 10

• The foetal lungs are filled with liquid (placenta at this point does the breathing). The fluid is produced by the foetal lung itself and is needed for lung maturation but it has to be in the correct volume.
• By midgestation, the foetal lung contains around 4-6mls/kg and by term this has increased to 20mls/kg. The baby is producing this at a rate of 2mls/kg/hr that by term has increased to 5mls/kg/hr.

Question 11

Composition of lung liquid compared to plasma and amniotic

Answer 11

• Lung liquid is unique in its composition. In terms of Na+ and K+ concentrations it is similar to plasma levels but Cl- in the lung liquid is much higher and HCO3- is substantially lower as well as there being very small amount of proteins compared to plasma.
• Amniotic fluid is mostly produced from foetal urine so has high K+ and Cl- compared to plasma.

Question 12

Describe mechanism of the secretion of lung liquid

Answer 12

• The lung liquid component is produced by active pumping out of chloride from the interstitium into the lumen of the lung via secondary active transport.
  As the amount of chloride increases in the lumen, Na+ moves across passively and H2O follows by osmosis passively.

Question 13

What is the function of lung liquid production?

Answer 13

• This liquid production allows for a positive pressure in the lung of 1cmH2O and this distending pressure keeps the lung open.
• The lung fluid is required for lung growth but not branching, so problems with lung fluid will affect its function rather than structure.

Question 14

Describe mechanism of the adsorption of lung liquid

Answer 14

• The lung has to then adapt in order to allow the baby to survive extrauterine life. Therefore the fluid needs to be absorbed. This occurs before birth.
• This is done through active Na+ pumping at the apical/luminal membrane into the cell out of the lung lumen. It then gets secreted into the intersitium by the 3Na+/2K+ transporter.
  Chloride and water then follow passively out of the lung lumen and into the interstitum.
• During labour and delivery, release of adrenaline starts stimulates these Na+ transporters to work hard to pump Na+ out of the lumen and into the interstitium.
• Prior to this thyroid hormone and cortisol are required for the maturation of the lung and these transporters so that they will respond to adrenaline.
• Upon delivery, exposure to postnatal oxygen will further increase Na+ transport across the pulmonary epithelium, out of the lung and into the interstitum.

Question 15

List pathologies associated with lung liquid

Answer 15

• Oligohydramnios.
• Foetal breathing abnormalities.
• Transient tachypnoea of the newborn (TTN).

Question 16

Describe lung liquid role in Oligohydramnios

Answer 16

• Oligohydramnios may occur due to an early rupture and or kidney abnormalities of the foetus. - As there is less amniotic fluid, the fluid pressure in the lungs (1cmH2O) starts to get pushed out of the lung and the lungs become short of fluid.
• This makes the lung hypoplastic (underdeveloped) and the vasculature develops abnormally. Baby can also end up being restricted and unable to move in the uterus.
• Antenatal steroids help with this.

Question 17

Describe lung liquid role in foetal breathing abnormalities

Answer 17

The neuromuscular tone of the respiratory system allows the foetus to have normal breathing movements. However if this tone is lost it can cause liquid to be lost from the lung as the pressure is lost. This may be caused by:

• Neuromuscular disorders
• Phrenic nerve agenesis
• CDH (diaphragmatic hernia)

Question 18

Describe Transient Tachypnoea of the Newborn (TTN)

Answer 18

This can occur when there is delivery without labour and mother opts to have an elective caesarean section. The baby the signals that it should stop secreting fluid and start reabsorbing fluid. This is because the mother doesn’t go through the transitional period and produce the steroids/adrenaline so the pumps are not as effective.

Question 19

Describe the synthesis, release and degradation of surfactant

Answer 19

• Surfactant is produced by type 2 pneumocytes.
• The main component of is surfactant phosphatidylcholine (PC) and this is produced in the endoplasmic reticulum.
• It is then stored in the type 2 pneumocytes in structures called lamellar bodies.
• Surfactant is then degraded in the alveoli and absorbed and recycled by the alveolar cells.
• 90% of the PC produced by the pneumocyte is reprocessed and turns over so very little is lost. The turnover time is about 10 hours during which entire surfactant is replaced.

Question 20

What stimulates surfactant release?

Answer 20

• There is negative feedback system to regulate the release of surfactant and this comes from stretch receptors.
• Similarly there are B adrenergic receptors on the type 2 pneumocytes and stimulation of these will cause surfactant release. The number of B adrenoceptors increases with gestation, this allows them to be more receptive to stimuli allowing them to produce more surfactant.

Question 21

What does surfactant do?

Answer 21

• Reduces the surface tension of the lung/alveoli and by doing this it prevents the alveoli from collapsing. If the alveoli did keep collapsing it would damage the wall of the alveoli and this would cause inflammatory reactions.
• Surfactant thus also prevents atelectasis (incomplete inflation of lung) and reduces the work to breathe.
• It is solid at body temperature and becomes a solid monolayer that stabilises alveoli as it is made out of tubular myelin at 37 degrees.

Question 22

Describe tubular myelin

Answer 22

• Highly organised structure.
• When compressed transforms from gel to liquid crystal phase.
• Surface tension approaches zero.
• At 37 degrees surfactant forms tubular myelin.
• As phospholipid bilayer is compressed, there is less water exposed therefore reducing surface tension and preventing further collapse of alveoli.

Question 23

Describe the structure of pneumocytes in the alveoli

Answer 23

• The bottom is the capillary endothelum and the basal lamina is on top. The type 1 pneuomocytes sit on the basal lamina. These have a tin lining so there is easy diffusion and out of them into capillaries.
• There are also the larger type II pneumocytes sitting within the alveolar wall.
  The type II pneumocytes produce fluid and a structure called tubular myelin that forms a hypophase across the inside of the alveolar surface facing the alveolar gas. This is what keeps the alveolus open.

Question 24

Describe the mechanism of the cycle of surfactant production and degradation

Answer 24

1. Precursors enter into the type II pneumocyte, combine with components in the cell and surfactant is produced in the endoplasmic reticulum
2. Surfactant stored within the type II cell in lamellar bodies.
3. Lamellar bodies secreted and form into a tubular myelin framework that lines the inside of the alveolus. This keeps the alveolus open.
4. Surfactant then gets degraded by macrophages and broken up particles get taken back into the type II cell degraded further while some is recycled.
5. Some choline fatty acids are lost while phospholipids get reused. Remember 90% are recycled.

Question 25

Describe surfactant composition

Answer 25

Surfactant itself is a mix of phospholipids, neutral lipids and protein.

• The phosphatidylcholine (PC) makes up 80% while the phosphatidyl glycerol (PG) is about 10% of the lipid present.
• 60% of the PC is disaturated, this is dipalmitoyl phosphatidylcholine (DPPC) and is the major component of surfactant (makes up 50% by mass). It is this DPPC that reduces the surface tension while PG promotes spreading of the surfactant throughout the lungs.
• Other lipids in surfactant include neutral lipids like cholesterol, these help alter the fluidity of the membrane

Question 26

What are the 4 main proteins in surfactant?

Answer 26

SP-A
SP-B
SP-C
SP-D
These make up 5-10% of surfactant by weight

Question 27

Describe SP-A

Answer 27

Is a large glycoprotein (the largest SP) that is coded for by a gene on chromosome 10 and is only expressed in the lung. From 28 weeks onwards the production of SP-A increases significantly. Thus if born before 28wks both quantity and composition of surfactant will be different, thus so will its function.
It is essential in:
- Determining the structure of the tubular myelin.
- The stability and spreading of the phospholipids in surfactant.
- As part of the -ve feedback loop.

Question 28

Describe SP-B

Answer 28

Makes up only 1-2% of surfactant by weight and is coded for by a gene on chromosome 2. Glucocorticoids increase its expression. It is required for:

• Formation of the tubular myelin .
• Spreading of the phospholipids across the alveolar membrane.
• When combined with lipid mixtures most of the surface activity in vitro and it increases lung compliance in vivo.
• It also protects the surfactant film from inactivation by serum proteins (this is important once baby is born).

Question 29

Describe SP-C

Answer 29

Located on chromosome 8, only 38 amino acids long. It significantly enhances absorption and spreading of the phospholipids.

Question 30

Describe SP-D

Answer 30

Is different to the other SP, it doesn’t have a structural function (no sig. surfactant activity) rather it has an immune function in protecting the surfactant from external pathogens. Its expression is widely distributed in epithelial cells and its expression is increased with gestation.

Question 31

Describe the factors that are important in the maturation of surfactant during uterine life

Answer 31

• Glucocorticoids are probably the most important, there is increased production of them towards the end of gestation and it increases the percentage of DPPC. If you give dexamethasone it enhances the expression of the β2-adrenoceptor gene and thus it leads to increased surfactant production and release.
• Thyroid hormones are also quite important, T4 increases surfactant production, T3 crosses placenta and TRH which increases phospholipid independent of T3 + T4.
• Insulin on the other hand has a negative impact. It delays the maturation of type II cells and decreases the amount of saturated PC.
  It also delays production of PG. Thus it is understandable that maternal diabetes, leads to poor glucose control, the foetus will end up with high glucose. As a result it will increase insulin release and this will make the baby fat and they have delayed lung maturation (so increased sugar levels delay lung maturation).

Question 32

Describe how prematurity impacts on the lungs ability to function outside the uterus (this is a type of surfactant pathology)

Answer 32

• Before 23 weeks there are very few type II pneumocytes and the alveoli are very poorly formed. This is why the threshold of viability hasn’t moved beyond about 23/24 weeks.
• After 24 weeks the foetus becomes viable from a respiratory point of view.
• Before 28wks there is very little surfactant the surfactant produced is relatively unsaturated this means it is stiff and unstable and more likely to buckle on expiration.
• PG also replaces PI with gestation and PG is important for the spreading of the phospholipids, so an earlier delivery means less PG.
• There is also leaky capillary membranes meaning that there is leakage of serum proteins in the lungs. Also fibrin deposition. There is formation of hyaline membranes across alveolar membrane that reduces diffusion of gases into capillaries.

Question 33

Describe SP deficiencies in surfactant pathology

Answer 33

SP-B absence leads to markedly reduced PG, as are result there is no secretion of normal surfactant and is lethal. Luckily lung transplants are possible for some if they have reduced SP-B.
SP-C deficiency is often seen in interstitial lung disease.

Question 34

Describe the adaptations the baby (for lungs) needs to undergo at birth to survive extra uterine life

Answer 34

• Once the foetal lung is exposed to adrenaline at birth, the volume of lung liquid rapidly starts to decrease. During labour the lung liquid production stops and there is a switch to reabsorption. Cooling during labour along with other stimuli will stimulate the baby to start breathing. Central chemoreceptors will detect hypoxia. The median time from delivery to first breath is 10 seconds and this is a deep breathe with a high inspiratory pressure (helps clear last bits of liquid in lung) and then active expiration with high pressure.
• Air replaces fluid in the lungs within minutes after delivery, some is squeezed out. Most fluid gets absorbed in the lymphatics (takes 1hr) and the capillaries (over 6-24hrs).
  This removal of fluid results in a rapid fall in airway resistance and an increase in FRC, the resting lung volume required to breathe.
  The increase in compliance is slower and takes about 24hrs.
• The whole process starts before birth, so that at birth the lung is good enough to breathe.

Question 35

Describe the regulation of breathing in babies

Answer 35

• The baby also needs to be able to regulate its actual breathing, this is done by the VRG and DRG and pneumotaxic areas. These are in the ventrolateral brainstem (where the respiratory centre is). Stimulated by CO2.
• Normal breathing rhythm is active inspiration but passive expiration, although active can be used.

Question 36

Describe the differences in the control of breathing between different ages.

Answer 36

• Adults as they become more hypoxic they start to breathe faster and harder until they reach a plateau. Children follow a similar pattern but just a lower plateau.
• When a foetus is exposed to hypoxia in utero the reverse occurs! Its breathing efforts decrease and come down to effectively not breathing until a stimulus comes.
• A term baby starts to increase its breathing effort with hypoxia but if it continues the term baby cannot continue and starts to hypoventilate.
• A preterm baby is in between, it has a small ability to breathe faster but will soon go down to hypoventilation when hypoxia is prolonged. This means if they suffer hypoxia during delivery it can be extremely dangerous.

Question 37

Why do premature babies breathe differently to adults

Answer 37

• Have less developed respiratory centres and can’t breathe very well.
• Very premature babies respond like a foetus and can go into apnoea when hypoxic during or after labour when in an incubator.
• Cold babies don’t have initial hyperventilation.
• Sometimes, premies just stop breathing. We try stop this by giving babies caffeine so that once delivered they breathe better and do not become hypoxic or respond to hypoxia by apnoea.

Question 38

Describe neurological adaptation of babies brain to hypoxia

Answer 38

• Labour is can be quite a hypoxic environment and so the baby is built to withstand labour as one would think it could lead to damage to the brain with prolonged hypoxia.
• Newborn brains utilise non-oxidative glycolysis and utilise ketone bodies, thus allows the brain to continue to obtain energy and function up until oxygen is present again.
• Baby also has fewer synapses so a lower O2 requirement (proposed).
• Hypoxia also leads to redirection of blood flow in the foetus towards the vital organs like brain, heart etc.
• Babies who have had an obstructed labour for a small amount of time may have some stomach issues as been hypoxic but brain should be preserved.
• If the hypoxic period extends beyond what the brain can cope with, then the brain will be hit.