Theme 4: Cardiorespiratory Physiology Flashcards
What is infant respiratory distress syndrome?
- Occurs in infants born pre-maturely (before surfactant is produced)
- It involves the lungs not filling properly and patchy collapse of parts of the lungs
What do the lungs fill with in infant respiratory distress syndrome?
Hyaline membrane -> This is a mix of fibrin with cellular debris
This has led to the condition also being referred to as “hyaline membrane disease”.
Give some experimental evidence for the importance of surface tension in the lungs.
(Neergaard, 1929):
- Plotted lung volume against pressure when inflating pig lungs with air and water
- Found that the lungs inflated at a lower pressure when using water to fill them
- He suggested that this was because the surface tension of the surfactant tends to pull the lung shut
(Mead, 1957):
- Carried out a similar experiment to (Neergaard, 1929), except also looked at the deflation of the lungs
- Found similar results and also noted that the lungs deflated more slowly than they inflated -> This property is called hysteresis
- Hysteresis was not seen when filling with saline, which suggests that surface tension may also be responsible for hysteresis
What is the surface tension in a bubble (water-air interface)?
Around 70mN/m
What equation can be used to deduce the pressure in an alveolus based on surface tension?
Laplace’s equation:
- P = 2T/r
- We can assume that tension is 70mN/m
- Hence, the smaller the radius, the larger the pressure in the alveolus (making it susceptible to collapse)
Describe the bubble model of alveolar (in)stability.
- Assuming that the surface tension in each alveolus is equal, the smaller the radius of an alveolus, the larger the pressure inside will be (according to Laplace’s equation: P = 2T/r)
- This means that air will move from the less inflated to the more inflated alveolus -> This will exacerbate the problem and potentially lead to collapse of some areas of the lung
- Hence, the idea of a surfactant is desirable because it reduces surface tension. When the radius of an alveolus reduces, the surfactant becomes more concentrated, so it reduces the pressure inside and allows the alveoli to revert to normal size.
Give some experimental evidence for the identification of surfactant.
(Brown, 1959):
- Used a setup to study surface tension
- Found that ground-up animal lung extract reduced the surface tension
(Brown, 1964):
- Identified the main component of surfactant as dipalmitoyl phosphatidylcholine (DPPC)
- The molecule has a polar head and a hydrophobic tail
- It is mostly lipid and it disrupts the bonds between water molecules that drive surface tension
What cells produce surfactant?
Type II epithelial cells
Draw a diagram to visualise the bubble model of alveolar (in)stability.
Note how the surfactant is on the INSIDE of the water layer.
Give experimental evidence FOR and AGAINST the bubble model of alveolar (in)stability.
FOR:
- (Bastacky, 1995):
- Produced a scanning electron microscopy image of rat lung
- This showed a thin and continuous water layer lining the the alveolus
- This is consistent with the bubble model of alveolar (in)stability
AGAINST:
- (Dorrington, 2001):
- Noted that the alveoli actually show a polygonal shape
- In a polygon-shaped alveolus, a continuous thin liquid layer would be inherently unstable and it would be redistributed
- However, this newly-redistributed fluid would ressemble what is seen in stable pulmonary oedema
Describe an alternative model to the bubble model of alveolar (in)stability. Give experimental evidence.
- (Hill, 1990):
- Noted that, not only could a spherical bubble of water not exist as the lining in a polygonal alveolus, but also that the surface tension would be pulling water from the alveolar walls into the lumen
- Hills instead suggested a model where the surfactant is hydrophobic and exists on the walls of the alveolus, but not the corners
- Therefore, fluid would only accumulate in the corners, helping keep the corners dry
- Since the fluid would form convexly in the corners, the surface tension would also act outwards, pushing fluid into the alveolar walls and helping to keep the alveolar lumen dry
However, there is also evidence against this model:
- (Weibel, 1979):
- Produced images that show fluid accumulation in the corners of the alveoli BUT in a concave shape, not convex
- (Bachofen, 1995):
- Produced images of the alveoli
- When extra fluid was added to the alveoli, they began to fill in a spherical shape
- This was evidence against the idea of hydrophobic surfaces
Another model that was suggested was the active pumping of water out of the alveoli:
- (Dorrington, 1995):
- Suggested that surfactant exists only in the corners of the alveoli next to type II epithelial cells, which secrete surfactant and reduce surface tension
- The rest of the lung is kept dry mostly by active absorption of water into the lung wall
Give experimental evidence for how water is actively absorbed in the alveoli.
(Crone, 1990):
- Suggested a model with 3 types of protein on the epithelial cells:
- Na+ channel (luminal side)
- Na+/K+-exchanger (wall side)
- Na+/glucose co-transporter
- Measured fluid loss from the lung under experimental conditions
- A control experiment with glucose showed greatest fluid loss, followed by the experiment with no glucose, followed by amiloride (Na+ channel blocker), followed by amiloride + no glucose
- This confirmed the importance of glucose and the epithelial sodium channel in fluid absorption
Draw a summary of the main models of alveolar stability.
What are the clinical implications of surfactant?
- Replacement of surfactant in infant respiratory distress syndrome
- Some surfactant proteins may also have an immunological role (Nathan, 2016)
What is the triad of general anaesthesia?
Describe how general anaesthesia affects ventilation-respiratory control.
- Diminishes pulmonary ventilation:
- This includes reduced tidal volume and respiratory reserve
- The amount of dead space may also be affected, which will affect CO2 control
- Opiates produce deep sighing breaths
- Increased physical obstruction of the airway due to reduced tone in the muscles that hold the airway open
- Reduced diaphragm and intercostal muscle action leads to reduces functional residual capacity
- Bronchodilation due to smooth muscle relaxation
- V/Q mismatch
Draw a graph to show how general anaesthesia affects the relationship between PaCO2 and ventilation.
Draw a graph to show how general anaesthesia affects the relationship between PaO2 and ventilation.
Describe how general anaesthesia affects the cardiovascular system.
- Reduced venous return -> Due to positive pressure ventilation, which makes it hard to get blood back into the lungs
- Reduced mean arterial pressure -> Due to vasodilation
- Reduced contractility of the heart
- Slight tachycardia
How can the unwanted effects of general anaesthesia be counteracted?
- Fluids
- Vasopressors
- Inotropes
Define shock.
- Shock is defined as a state of cellular and tissue hypoxia due to either:
- Reduced oxygen delivery
- Increased oxygen consumption
- Inadequate oxygen utilization
- This most commonly occurs when there is circulatory failure manifested as hypotension (ie, reduced tissue perfusion); however, it is crucial to recognize that a patient in shock can present hypertensive, normotensive, or hypotensive.
What are some physical signs of tissue hypoperfusion?
- Brain -> Altered mental state
- Skin -> Mottled, clammy
- Kidney -> Oliguria
- Heart -> Tachycardia
- Blood -> Elevated lactate
Is lactate related to anoxia and oxygen delivery?
No, this is a bit of a myth. In reality, lactate is involved in many processes and it is not an indicator of anoxia and oxygen delivery.
What are the 4 main types of shock?
- Distributive
- Hypovolaemic
- Cardiogenic
- Obstructive
How do the lungs deal with fluid accumulation in the alveoli? Give experimental evidence.
There must be an active transport process to remove fluid from the alveoli.
(Basset, 1987):
- Created a setup of an isolated rat lung connected to a circulation with an oxygenator and pump, with a perfusate in the circulation
- Filled the rat lung with an instillate containing albumin, so that the albumin concentration could be used to measure absorption of the fluid into the circulation
- Measured liquid absorption
- Ouabain and amiloride reduced absorption
- Repeated the experiment with a donor rat in the circuit and used a blood perfusate
- Amiloride and no D-glucose reduced absorption
- This led to the suggestion of this model
(Vejlstrup, 1994):
- Created a setup where one rabbit lung was filled with an isosmotic instillate, allowing fluid absorption or secretion to be measured
- Alveolar pressure was varied by altering the amount of fluid in the reservoir above the lung
- Found that fluid uptake was relatively unaffected by alveolar pressures until higher alveolar pressures
- When amiloride and phloridzin were used to block sodium transport, liquid uptake fell and was linearly related to the alveolar pressure -> At very low alveolar pressures, there was even some fluid secretion into the alveoli
- The conclusion was that the lung is in a state in which it would fill up with liquid from the blood stream were it not for the presence of an active transport mechanism that ensures a movement of liquid in the opposite direction.
How could fluid absorption from the alveolar space be altered in cardiogenic lung oedema? Give experimental evidence.
- Cardiogenic lung oedema is classically thought to be a mechanical issue, where heart failure leads to increased pulmonary venous and capillary pressures, so that fluid is forced out
- But recent experiments suggest that the situation may be more complex
- (Solymosi, 2013):
- Suggest that the hydrostatic pressure in the capillaries leads to NO release, which leads to downregulation of ENaC channels
- This leads to a reversal of the electrical gradients across the membrane and hence reversal of Cl- transport
- This drives fluid secretion into the alveolar space
Draw a diagram to show the factors that contribute to breathlessness.
Describe the relationship between breathlessness and lung function. Give experimental evidence.
(Herigstad, 2015):
- Found no correlation between breathlessness and lung function
Are variations in physiology and health (in terms of breathlessness) related to distinct brain networks? Give experimental evidence.
(Luettich, unpublished):
- Looked at over 19,000 individuals on the BioBank register, with around 2,500 of these having asthma and 250 having COPD
- Looked at interoceptive brain areas using FMRI, so that it could be determined whether there were differences in connectivity between healthy and asthmatic patients
- Also looked at 159 relevant non-imaging measures, such as pulse rate, smoking, etc.
- Used canonical correlation analysis to test for associations between brain connectivity and the 159 non-imagin measures
- Found 4 different modes of variation that explained the population
- 2.5% of the variance was explained by the breathing parameter (mode 2)
(Finnegan, 2021):
- Looked at the results of 23 different questionnaires filled in by patients with COPD
- Peformed correlation analysis to see whether the different questionnaires related to each other
- Found 4 subsections of questionnaires that produced similar results:
- Mood
- Illness burden (symptoms)
- Ability (physical)
- Ability (anticipated)
- Using these 4 factors, the population could be split into a more impaired and less impaired group
- These could be explained by difference in brain activity, suggesting that indeed differences are not explained by differences in pulmonary function, but by differences in cognitive factors
(Finnegan, unpublished):
- Found that imaging and non-imaging measures alone were poor predictors of outcome in pulmonary rehabilitation
- However, when these two factors are combined, they are a good predictor of outcome
Give a summary of systemic iron homeostasis.
- FPN = Ferroportin
- Tf = Transferrin
- Hepcidin inhibits iron uptake by ferroportin, promoting its storage instead
Give a summary of cellular iron homeostasis.
- Uptake -> Mostly via the transferrin receptor
- Export -> Mostly via ferroportin
- Storage -> Iron is stored within ferritin (which is like a cage)
- Usage
When iron levels drop low, transferrin receptor expression is upregulated, and ferritin and ferroportin expression is downregulated.
When iron levels are too high, the opposite happens, which limits the formation of ROS.
How is cellular iron sensed?
IRP1:
- When iron is abundant, it contains iron-sulphur clusters, which enables it to acts in the TCA cycle
- When iron is low, the conformation of the IRP1 changes, allowing it to bind RNA
IRP2:
- When iron is abundant, it is degraded by FBXL5 (which only functions in the presence of iron and oxygen)
- When iron is low, the IRP2 binds RNA
IRP1 and IRP2 inhibit translation of proteins involved in storage, usage and export of iron, while stabilising the translation of proteins involved in uptake of iron.
What do IRP1 and IRP2 bind to?
Iron regulatory elements (IREs), which are hairpin loops in RNA.
Give a summary of how iron deficiency affects the cardiorespiratory system.
Iron not only affects the system via causing anaemia, but also by direct effects on organs due to cellular iron deficiency.
Describe the haemodynamic mechanisms that underpin how iron deficiency affects the myocardium.
- Severe chronic anaemia leads to peripheral vasodilation, which reduces blood pressure
- This leads to catecholamine release and activation of the RAA axis, as well as natriuretic peptide release
- This leads to decreased renal blood flow and glomerular filtration rate
- Hence there is salt and water retention
- This leads to increased plasma and extracellular volume, which increases work on the heart
- This eventually leads to worsening heart failure, which in turn drives the anaemia again
Describe the local mechanisms that underpin how iron deficiency affects the myocardium.
- Haemoglobin and myoglobin synthesis are reduced due to the iron deficiency -> This means that there is not only impaired oxygen delivery but also impaired oxygen storage in the myocardium
- Iron deficiency also leads to decreased activity in the Krebs cycle and ETC, since many of the enzymes require iron
- Hence, there is energetic failure in the myocardium, which is a precursor to heart failure
- Energetic failure may occur even when there is abundant oxygen because low iron leads to upregulated HIF -> This drives a shift towards glycolysis, which in the long-term is a maladaptive response
Draw a summary of the effects of iron deficiency on the heart.
Give some experimental evidence for the role of iron in normal pulmonary responses to hypoxia.
(Smith, 2008):
- Exposed participants to 2 acute periods of hypoxia before and after an 8 hour period of prolonged hypoxia
- Prior to this, they received an infusion of iron or saline
- In the saline group, the second period of acute hypoxia resulted in a greater pulmonary hypertension than the first period
- In the iron group, both periods of acute hypoxia resulted in a similar pulmonary hypertension (of same magnitude as the first period in the saline group)
- Repeated this protocol without an prior infusion and replaced the 8 hour hypoxia with an 8 hour infusion of either saline or DFO (an iron chelator)
- In the saline group, both periods of acute hypoxia resulted in a similar pulmonary hypertension
- In the DFO group, the second period of acute hypoxia resulted in a greater pulmonary hypertension than the first period
- Thus, the iron deficiency produced a similar effect to prolonged hypoxia
(Smith, 2009):
- Studied participants ascending to an altitude of 4340m
- Pulmonary arterial pressure rose within the first day
- On the third day, some of the participants were given a placebo and some were given iron
- The iron led to lower pulmonary arterial pressures over the next 4 days
(Frise, 2016):
- Studied the pulmonary arterial pressure of patients receiving saline infusion during a period of hypoxia (over a period of hours)
- Those with clinical iron deficiency showed greater pulmonary hypertension than the controls
- When this was repeated with prior iron infusion instead of saline, the pulmonary pressure rose and then began to fall after 2 hours in both groups, with much lesser pulmonary hypertension in both groups
- This could not be due to an effect on haemoglobin since the response is too fast
Compare the effects of acute and chronic hypoxia on the pulmonary arteries. How does iron relate to this?
- The effects of acute hypoxia are easily reversed and iron can help with this
- Chronic hypoxia can lead to irreversible changes
- Iron deficiency could be a contributor to the mechanisms that lead to chronic hypoxia-induced pulmonary arterial hypertension
Give experimental evidence for the importance of iron deficiency in idiopathic pulmonary arterial hypertension.
(Rhodes, 2011):
- Divided a population with PAH into those with a soluble transferrin receptor (sTfR) under 28.1 and those over 28.1
- An sTfR over 28.1 is a sign of iron deficiency
- The iron deficiency group showed lower cumulative survival over the next 7 years of follow-up
(Kramer, 2021):
- Studied the use of intravenous iron supplementation in idiopathic PAH
- The iron supplementation led to a reduction in PAH-associated hospitalisation
Why does iron deficiency lead to increased endothelin-1?
Draw a summary of the effects of iron deficiency on the pulmonary circulation.
Summarise the clinical implications of iron deficiency.
