15. Lung Development

Question 1

What are the 3 main functions of the lung?

Answer 1

Ventilation

Diffusion

Perfusion

Question 2

Outline the embryonic development of the lungs

Answer 2

The tracheal bud forms from the foregut at 4-5 weeks of gestation

By 16 weeks gestation, bronchial branching is complete:

o Pulmonary artery branching then follows this

Alveolar development continues until 8-10 years of age

Hypoplastic lung; interruption to bronchial branching leads to the development of a small lung with little branching:

o Isotope ventilation scan will show poor air supply to the lung

o Isotope perfusion scan will show poor artery development

Question 3

Outline embryogenesis in relation to the lungs

Answer 3

Different tissues develop at different rates

Bronchial buds are supplied by systemic vessels:

o Systemic vessels regress as the pulmonary artery takes over principle supply

The bronchial artery development occurs independently from the aorta

Insult to this development (e.g. infection, vascular accident, trauma) may result in malformation depending upon the timing of the insult rather than its nature

Theoretical ‘insults’ to either of the dividing bronchi may lead to malformations including agenesis (early malfunction), a local lesion (impact to specific area), malformation of systemic supply to ‘normal’ lung or ‘abnormal’ lung, or a malformation in the lung leading to normal pulmonary artery supply to abnormal lung

Question 4

Outline the main influences on lung development

Answer 4

Hox genes

Transcription factors

Autocrine and paracrine interactions

Peptide growth factors

Thoracic cage volume

Lung liquid positive pressure

Amniotic fluid volume

Maternal nutrition (e.g. Vitamin A)

E.g. of restricted lung volume: Diaphragmatic hernia (of Bochdalek) leads to hypoplasticity

Question 5

Outline Hox genes

Answer 5

Hox genes, a subset of homeotic genes, are a group of related genes that control the body plan of an embryo along the head-tail axis

Question 6

Outline pulmonary hypoplasia

Answer 6

Pulmonary hypoplasia (PH) is the incomplete development of the lungs, resulting in an abnormally low number or size of bronchopulmonary segments or alveoli

A congenital malformation, it most often occurs secondary to other foetal abnormalities that interfere with normal development of the lungs

Primary (idiopathic) pulmonary hypoplasia is rare and usually not associated with other maternal or foetal abnormalities

Causes of pulmonary hypoplasia include a wide variety of congenital malformations and other conditions in which pulmonary hypoplasia is a complication; these include congenital diaphragmatic hernia, congenital cystic adenomatoid malformation, foetal hydronephrosis, caudal regression syndrome, mediastinal tumor, and sacrococcygeal teratoma with a large component inside the foetus

PH is a common direct cause of neonatal death resulting from pregnancy induced hypertension

Pulmonary hypoplasia is associated with oligohydramnios through multiple mechanisms; e.g. both conditions can result from blockage of the urinary bladder

Medical diagnosis of pulmonary hypoplasia in utero may use imaging, usually ultrasound or MRI

Question 7

Define idiopathic

Answer 7

Relating to or denoting any disease or condition which arises spontaneously or for which the cause is unknown

Question 8

Outline Bochdalek hernias

Answer 8

A Bochdalek hernia is one of two forms of a congenital diaphragmatic hernia, the other form being Morgagni hernia

A Bochdalek hernia is a congenital abnormality in which an opening exists in the infant’s diaphragm, allowing normally intra-abdominal organs (particularly the stomach and intestines) to protrude into the thoracic cavity

In the majority of patients, the affected lung will be deformed, and the resulting lung compression can be life-threatening

Question 9

Outline airways branching

Answer 9

NB: with regards to the cartilaginous rings in the trachea and bronchi/bronchioles, the only complete ring is the circhoid in the larynx

With increased branching, there are an increased number of alveoli, ducts, neural network and smooth muscle development; this is to allow the necessary bronchoconstriction and dilation

There are 25 generations of branching which occurs during pre-natal development

Pre-natal development consists of 3 development stages:

• Glandular
• Canalicular
• Alveolar

The development of a foetal airway at 10 weeks gestation leads to pressure changes in the thorax

This has a trophic effect on development, leading to the expression of a gene which stimulates the branching of the airway

Question 10

Outline respiratory insult during maternal pregnancy (e.g. smoking)

Answer 10

Causes increased respiratory movements and changes in thoracic pressures, while removing some of the soft tissue support and interstitial tissue development

Reduces elasticity of the alveoli, leading to reduced support

Reduces airway diameter, leading to reduced support, leading to a wheezy infant (4x increased risk of infant wheeze), leading to COPD
at old age

Summary: reduced lung function at birth

Question 11

Outline the foetal circulation

Answer 11

Mostly bypasses the lungs, as they are not fully developed

From the placenta, blood enters the left atrium from the right atrium through the open foramen ovale:

o From the right atrium, it enters the right ventricle; from the right ventricle, some goes to the lung via the pulmonary trunk, but most goes to the aorta via the ductus arteriosus; this is because the pulmonary arterial pressure is greater than the systemic arterial pressure, and the pressure gradient drives the movement of the blood

Only approximately 10% of foetal blood is transported to the lungs

pH of blood =7.2 (norm is 7.4)

pO2 = 3.4kPa (norm is 10)

pCO2 = 7-8kPa (norm is 5.3)

Question 12

Outline the ductus arteriosus

Answer 12

In the developing foetus, the ductus arteriosus, also called the ductus Botalli, is a blood vessel connecting the main pulmonary artery to the proximal descending aorta

It allows most of the blood from the right ventricle to bypass the foetus’ fluid-filled non-functioning lungs

Upon closure at birth, it becomes the ligamentum arteriosum

There are two other foetal shunts, the ductus venosus and the foramen ovale

Question 13

Outline the lungs at birth

Answer 13

Massive CNS stimulation due to change in environment

Low pressure in the placental circulation is cut, leading to a rise in systemic arterial pressure

Lung aeration causes a fall in pulmonary arterial pressure (as the lungs stretch), increasing the pO2 and decreasing the pCO2, ensuring that:

Systemic pressure > pulmonary pressure

The ductus arteriosus closes due to changes in prostaglandins

An increase in left atrial pressure (due to a rise in systemic arterial pressure) causes the foramen ovale to close

Question 14

Outline the foramen ovale

Answer 14

In the foetal heart, the foramen ovale, also foramen Botalli, allows blood to enter the left atrium from the right atrium

It is one of two foetal cardiac shunts, the other being the ductus arteriosus (which allows blood that still escapes to the right ventricle to bypass the pulmonary circulation).

Another similar adaptation in the foetus is the ductus venosus

In most individuals, the foramen ovale closes at birth; it later forms the fossa ovalis

Question 15

Outline the ductus venosus

Answer 15

In the foetus, the ductus venosus shunts a portion of the left umbilical vein blood flow directly to the inferior vena cava

Thus, it allows oxygenated blood from the placenta to bypass the liver

In conjunction with the other foetal shunts, the foramen ovale and ductus arteriosus, it plays a critical role in preferentially shunting oxygenated blood to the foetal brain

Question 16

Outline the lungs on the first day post-birth

Answer 16

Pulmonary vasodilatation increases 5-fold, increasing the pulmonary blood-flow

This resets the chemo-receptors and respiratory centres

Aeration of the lungs occurs; there is high positive expiratory pressure, and the lung volume rises to optimum

Within the first 2 hours, airway resistance falls

However, the rise in lung compliance takes at least 24 hours

The lymphatic system is relied upon to remove the fluid which is filling lungs, but this is slow therefore the lungs remain stiff until the fluid is removed

pO2 increases and pCO2 decreases, leading to an increased pH of the blood

Question 17

How does a foetus cope with the decreased pO2?

Answer 17

The Hb saturation curve is different, therefore has increased oxygen-binding capacity at lower partial pressures

This is known as the Bohr shift/effect

The Bohr effect is a physiological phenomenon first described in 1904 by the Danish physiologist Christian Bohr; haemoglobin’s oxygen binding affinity is inversely related both to acidity and to the concentration of carbon dioxide

Since carbon dioxide reacts with water to form carbonic acid, an increase in CO2 results in a decrease in blood pH, resulting in haemoglobin proteins releasing their load of oxygen

Conversely, a decrease in carbon dioxide provokes an increase in pH, which results in haemoglobin picking up more oxygen

Question 18

Outline obstruction of breathing

Answer 18

Asphyxia:

o At birth, attempted breathing occurs; with umbilical strangulation, gasping fails; this is called primary apnoea

o 2nd attempt at breathing (with failure of successful ventilation) results in a decreased blood pressure; heart rate is relatively maintained; this is known as terminal apnoea

Resuscitation:

o Required if the delivery of oxygen fails following terminal apnoea

o Results in an increase in heart rate and blood pressure

Apgar score:

o Used to determine the severity of apnoea and need for resuscitation etc.

o It measures heart rate, respiration, muscle tone, response to a pharyngeal catcher and the colour of the trunk

Question 19

What can go wrong in lung development?

Answer 19

In a normal foetal human lung, pulmonary surfactant (phospholipid produced by epithelial cells) is released from lamellar bodies:

o Once secreted, the lamellar bodies create a force resulting in the distension (swelling) and maintenance of distension of the airways at lower pressures therefore the airways remain open

o Surfactant is only generated in the late 2nd and early 3rd trimester; therefore premature babies carry risk of alveolar collapse, which leads to hypoventilation and hypoxic acidosis, leading to pulmonary vasoconstriction and right-to-left shunting

o This is known as Idiopathic Respiratory Distress Syndrome; as this starts to develop, the baby will ‘grunt’ to try and raise pressure and hold the airways open when breathing out

o Continuous ventilation is then required, but now surfactant can be replaced

Cilia beat in a coordinated fashion moving material out of the airway to prevent infection:

o Malfunction of their movement leads to right lower lobe collapse, dextrocardia and possible total situs invertus

o This is known as Kartagener’s syndrome (or ‘primary cilia dyskinesia’)’ it shows that the orientation of organ development it utero is dependent on cilia function

Question 20

Define shunting

Answer 20

A condition in which blood, by going through an abnormal pathway or bypass, does not travel its normal route

It may occur when an arteriovenous fistula forms or in congenital anomalies of the heart in which the blood passes from the right atrium or ventricle directly to the left atrium or ventricle respectively, through a defect in the wall (septum) that normally separates the atria and ventricles

Question 21

Outline pulmonary surfactant

Answer 21

Pulmonary surfactant is a surface-active lipoprotein complex (phospholipoprotein) formed by type II alveolar cells

The proteins and lipids that make up the surfactant have both hydrophilic and hydrophobic regions

By adsorbing to the air-water interface of alveoli, with hydrophilic head groups in the water and the hydrophobic tails facing towards the air, the main lipid component of surfactant, dipalmitoylphosphatidylcholine (DPPC), reduces surface tension

Question 22

Define fistula

Answer 22

A fistula is an abnormal connection between two hollow spaces (technically, two epithelialized surfaces), such as blood vessels, intestines, or other hollow organs

Fistulas are usually caused by injury or surgery, but they can also result from an infection or inflammation

Question 23

Outline situs inversus

Answer 23

Situs inversus (also called situs transversus or oppositus) is a congenital condition in which the major visceral organs are reversed or mirrored from their normal positions

The normal arrangement of internal organs is known as situs solitus while situs inversus is generally the mirror image of situs solitus.

Question 24

Outline dextrocardia

Answer 24

Dextrocardia is a rare heart condition in which your heart points toward the right side of your chest instead of the left side. Dextrocardia is congenital, which means people are born with this abnormality

Medical diagnosis of the two forms of congenital dextrocardia can be made by ECG or imaging

Dextrocardia is believed to occur in approximately 1 in 12,019 pregnancies

Question 25

How is lung function measured?

Answer 25

Forced expiratory measurements can be made using a pneumotachograph

Shown in a flow-volume loop; reduced lung function is therefore seen as a change in the loop seen

The pneumotachograph shows a volume/time curve; the Y-axis shows volume in litres whereas the X-axis shows time in seconds; a ‘flow-volume loop’ graphically depicts the rate of airflow on the Y-axis and the total volume inspired or expired on the X-axis

Question 26

Outline the evolution of post-natal lung function

Answer 26

During development from infant to old adult, there is a loss of alveolar elasticity, leading to reduced lung compliance:

o Compliance in infants and the elderly is more similar, therefore extremes of age pose an increased susceptibility to problems

With increasing age, as lungs develop lung function increases; however this is only up to a certain point, where it begins to decrease again; smoking increases the rate of this decrease:

o Early respiratory disease reduces overall lung function throughout life, therefore a combination of early respiratory disease and smoking will leads to overall reduced lung function and more rapid deterioration of lung function with increased age

Increased birth weight results in an increased lung function at late adult life, therefore premature babies carry an increased risk of reduced lung function