What are the 5 stages in the timeline of lung development?
Embryonic, pseudoglandular, canalicular, saccular/alveolar, postnatal
What is the embryonic phase of lung development?
Lasts 0-7wks -> lung buds form, main bronchi form
What is the pseudoglandular phase of lung development?
Lasts 5-7wks -> conducting airways, bronchi and bronchioli are formed
What is the canalicular phase of lung development?
Lasts 16-27 weeks -> respiratory airways and blood-gas barrier forms
What is the saccular/alveolar phase of lung development?
28-40wks -> alveoli appear
What is the postnatal phase?
Occurs until adolescence -> alveoli multiply and enlarge in size with chest cavity
In which lung development phases does vasculogenesis, branching and morphogenesis occur?
Embryonic and pseudoglandular
In which lung development phases does the blood gas barrier form?
In which lung development phases does alveo and angiogenesis occur?
When does the majority of the complex airway and circulatory system grow?
During early foetal life -> alveoli appear before birth and continue to grow in early childhood
What is Scimitar syndrome?
Anomalous pulm venous drainage of right lung to the IVC, unusually close to the junction of the right atrium
What can scimitar syndrome lead to?
Associated right lung and right pulmonary artery hypoplasia; dextrocardia; anomalous systemic arterial supply (which can form heart disease)
What happens during embryogenesis?
Much of the airway is let down -> bifurcation occurs, and by 7wks you have the correct lobes of the lungs
What happens in the pseudoglandular phase?
Branching morphogenesis of airways into mesenchyme; preacinar airways all present by 17 weeks; development of cartilage, smooth muscle and glands continues into canalicular phase
What are bronchial cartilage and how do they change with age?
Incomplete rings posteiorly, with irregular plates -> calcify with age
How can bronchial cartilage become malacic?
Generalised: laryngotracheomalcia. Localised: malacic segment
What is laryngomalacia?
Floppy/collapsible larynx -> come together to close when swallowing but in laryngomalacia, the airway collapses on itself
How is branching morphogenesis driven?
Lung buds consistent i appearance during airway formation (5-17wks) -> epithelial cells at tips of buds (highly proliferative multipotent progenitor cells), so cells behind the tip divide and differentiate into the various cell types -> communication between epithelial cells in distal branching lung buds and surrounding mesenchyme
How is branching morphogenesis controlled?
Epithelial-mesenchymal interaction is essential for branching morphogenesis -> genetic and transcription factors are involved in early bud formation; after bifurcation a variety of growth factors are important
What are the growth factors in lung development?
Inductive: FGF (brnching morphogenesis), EGF (epithelial proliferation and differentiation). Inhibitory: TGF beta (matrix synthesis, surfactant production, inhibits proliferation of epithelium and blood vessels); Retinoic acid (inhibits branching)
What problems can occur when the pulmonary growth factors are not properly coordinated?
Primary ciliary dyskinesia
When does a circulation present in the foetus?
At 5 weeks gestation
What can go wrong during angio/vasculogenesis?
Congenital thoracic malformations
What is the prevalence of cystic pulmonary airway malformations?
1 per 8300-35000 -> diagnosed (mostly) on antenatal US screening
What is the pathogenesis of cystic pulmonary airway malformation?
Defect in pulmonary mesenchyma, abnormal differentiation 5-7th week; normal blood supply but can be associated with sequestration -> DOESN'T affect the whole lung
What are the signs of type 2 CPAM and what is the histology?
Multiple small cysts, may be associated with renal agenesis, CV defects, diaphragmatic hernia and syryngomyelia. Histology: bronchiolar epithelium with overgrowth, separated by alveolar tissue which was underdeveloped
What is congenital lobar emphysema/congenital large hyperlucent lobe?
Progressive lobar expansion -> underlying cause: weak cartilage, extrinsic compression, one way valve effect and alveoli expand
What is the prevalence of CLHL?
More common in LUL > RML > RUL; in males > females; CHD association
What is intralobar sequestration?
75% of pulmonary sequestrations; abnormal segment shares visceral pleural covering of lung with aortic blood supply and with no communication to bronchial tree -> lower lobe predominance
What can cause intralobar sequestration?
Chronic bronchial obstruction, chronic postobstructive pneumonia
What are the types of lung growth anomalies?
Agenesis (complete absence of lung and vessel). Aplasia (blind ending bronchus, no lung/vessel). Hypoplasia (bronchus and rudimentary lung present, all elements reduced in size and number)
What are the symptoms of agenesis of lung growth?
Caused by abnormal flow in 4th week -> associated with other pathology; causes mediastinal shift towards opaque hemithorax
What is the cause of hypoplasia of the lung?
It is common (usually secondary) -> main cause is lack of space due to intra/extrathoracic complications like: Hernia, chest wall pathology, oligohydramnios, lymphatic or cardiac mass OR lack of growth -> congenital thoracic malformation
How do the endothelial cells differentiate into blood vessels in the lungs?
VEGF is secreted by epithelial cells and stimulates endothelial differentiation, which occurs around the lung bud in the mesenchyme, coalescing to form capillaries (vasculogenesis); airways act as structural template
What are some growth factors that control early blood vessel growth?
VEGF (prod: epithelial cells throughout gestation). Flk-1 (deficiency results in no blood vessel development). IGF/IGFR (from 4wks prevents capillary development). eNOS (stimulates proliferation and tube formation). Angiopoietin (important in wall differentiation)
What happens when a new bifurcation occurs to the blood supply?
Newly formed endothelial tubes are added and the arteries and veins supplying these capillaries get longer
What should be present at the end of the pseudoglandular period?
All airways and blood vessels at levels of terminal bronchiolus are present -> appearance of lung changes as it reaches canalicular stage
What occurs during the canalicular stage?
Airspaces at periphery enlarge; thinning of epithelium by underlying capillaries allows gas exchange; epithelial differentiation into TI/II epithelial cells; surfactant first detectable at 24/25 weeks; blood gas barrier required for post-natal life
When do alveoli appear?
28-40 weeks appear and multiply up to 3yrs
How are the alveolar walls formed?
Saccule wall (epithelium on both sides with 2x capillary network, myofibroblast and elastin fibres along wall -> secondary septa develop from wall led by elastin produced by myofibroblast, capillary lines both sides with matrix in between -> capillaries have coalesced to form one sheet alveolar wall, thinner and longer with less matrix, with muscle and elastin still at the tip
What is a future problem that could occur in preterm birth?
Becoming more common and effects can't be ameliorated by surfactant; thought that maybe they could be a future risk group of COPD
How can preterm births catch-up growth?
May be scope for airway catch-up growth under some circumstances (when baby is appropriate gestational age - so weighs what they are meant to weigh), alveolar growth continues much longer than we thought, may be scope for alveolar recovery after preterm birth
What are the lungs like at birth in humans?
Volume small and related to body weight; all airways present and differentiated, 33-50% alveoli allow for normal gas exchange with blood-gas barrier same as in adults; most arteries and veins present
What changes occur at birth in blood vessels?
Decrease in pulmonary vascular resistance and 10x rise in pulmonary blood flow -> arterial lumen increases and wall thins rapidly, change in cell shape and cytoskeletal organisation not loss of cells -> once thinning occurs, arteries grow and maintain a relatively thin wall -> LOW pressure and LOW resistance pulm vascular system
What are the possible mechanisms to increase flow after birth?
Expansion of alveoli dilates arteries (direct physical effect); expansion stimulates release of vasodilator agents; inhibition of vasoconstrictors present during fetal like; direct effect of O2 on smooth muscle cells
How do the airways grow in childhood and adolescence?
Lung volume increases 30x; airways increase in length and width by 2-3x (symmetrically); dysanaptic growth during the early period (alveoli growing more than airways); structural elements of wall increase
How do the alveoli grow in childhood and adolescence?
Alveoli increase in no. up to 2-3yrs (maybe adolescence), with adult alveolar no.=300-600million; alveoli increase in size and complexity to increase SA until body growth complete after adolescence (20x); arteries, veins and capillaries increase alongside the alveoli (35x)
How is the pulmonary circulation different from the systemic one?
Systemic arteries are a lot thicker, with a smaller lumen; left ventricle has thicker walls as it needs to pump a longer distance -> right side of the heart, is thin because it doesn't need to pump far or against gravity; systemic=high pressure circuit
How does the circuit pressure differ between systemic and pulmonary circuits?
How does these variables differ between systemic and pulmonary circuits?
What are the 3 functions of the pulmonary circulation?
1) Gas exchange (O2/CO2). 2) Metabolism of vasoactive substances (ACE -> AngII [vasoconstrictor], Bradykinin). 3) Filtration of blood -> pulm. circulation filters emboli before the systemic arteries
What is an embolus?
Mass within the circulation capable of causing obstruction
What is an embolism?
Event characterised by obstruction of major artery
How does the pulmonary circulation filter the blood?
What are the pulmonary shunts and what are they used for?
Circumstances associated with bypassing the respiratory exchange surface -> Save the blood passing through the pulmonary circulation
What are some examples of pulmonary shunts?
Bronchial circulation (LA, LV, Aorta, PA, BA, BV, PV, LA then RHS -> pass through LHS of heart 2x). Foetal circulation (foramen ovalae, ductus arteriosus). Congenital defect (septal defect, which mixes arterial and venous blood)
What should and does happen to the pulmonary vascular resistance when Cardiac output is increased?
Pulm circulation is low resistance, high capacity circuit at Q of 5L/min -> instead of increasing the pressure, the blood vessels stretch so there isn't a change is MAP
How does perfusion of the lungs change with increasing CO?
Pulmonary arteries are more compliant that systemic arteries -> hence more perfusion when greater CO
What happens to vascular resistance when ventilation increases?
Inspiration compresses alveolar vessels and expiration compresses extra-alveolar vessels
What happens to vascular resistance when hypoxaemia occurs?
Systemic vascular response is vasodilation and pulmonary vascular response is vasoconstriction
When is the hypoxic response in pulmonary circulation beneficial?
During foetal development -> blood follows path of least resistance, high-resistance pulmonary circuit means increased flow through shunts, with first breath increasing alveolar PO2, dilating pulmonary vessels
When is the hypoxic response in pulmonary circulation detrimental?
Chronic obstructive lung disease -> Reduced alveolar ventilation and air trapping, so increases resistance in pulmonary circuit > leading to pulmonary hypertension, right ventricular hypertrophy and congestive heart failure
How does the pulmonary fluid keep balanced?
Plasma hydrostatic is the main force in the vessel pushing fluid into the interstitial space; interstitial hydrostatic pressure is basically 0, as no fluid builds up in a healthy individual; Plasma oncotic is a main sucking force of proteins in the blood, to move water into the capillary; Interstitial oncotic is a sucking force of proteins in the interstitial space, to move water into the interstitium -> net movement out of the capillary which is easily controlled by the lymphatic system
What happens if the lymphatic drainage in the lungs fail?
Fluid accumulates, causing oedema (can also be due to production exceeding maximum rate of clearance)
What does a mitral valve stenosis cause to the fluid balance in the lungs?
Increased plasma hydrostatic pressure, more fluid forced into interstitium -> lymph clearance is exceeded, so oedema occurs
What does hypoproteinaemia cause to the fluid balance in the lungs?
Plasma oncotic pressure reduced, less fluid drawn into capillary, so fluid accumulates in interstitium -> lymph clearance exceeded, so oedema
What does an infection cause to the fluid balance in the lungs?
Increases interstitial oncotic pressure, more fluid drawn out of capillaries , large net fluid movement out of capillary -> so lymphatic clearance exceeded, so oedema
What does cancer cause to the fluid balance in the lungs?
Blocked lymph vessels -> oedema