15. Lung Development Flashcards
What are the 3 main functions of the lung?
Ventilation
Diffusion
Perfusion
Outline the embryonic development of the lungs
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
Outline embryogenesis in relation to the lungs
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
Outline the main influences on lung development
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
Outline Hox genes
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
Outline pulmonary hypoplasia
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
Define idiopathic
Relating to or denoting any disease or condition which arises spontaneously or for which the cause is unknown
Outline Bochdalek hernias
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
Outline airways branching
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
Outline respiratory insult during maternal pregnancy (e.g. smoking)
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
Outline the foetal circulation
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)
Outline the ductus arteriosus
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
Outline the lungs at birth
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
Outline the foramen ovale
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
Outline the ductus venosus
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
Outline the lungs on the first day post-birth
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
How does a foetus cope with the decreased pO2?
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
Outline obstruction of breathing
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
What can go wrong in lung development?
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
Define shunting
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
Outline pulmonary surfactant
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
Define fistula
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
Outline situs inversus
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.
Outline dextrocardia
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
How is lung function measured?
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
Outline the evolution of post-natal lung function
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
