Respiratory Flashcards
1
Q
Define minute volume?
A
5 litres of air a minute moved by the respiratory pump
2
Q
Define Transpulmonary pressure (Ptp)?
A
difference in pressure between the inside and
outside of the lung (alveolar pressure - intrapleural pressure)
3
Q
Define Intrapleural pressure (Pip)?
A
the pressure in the pleural space, also known as
intrathoracic pressure
4
Q
Define Alveolar pressure (Palv)?
A
Air pressure in pulmonary alveoli
5
Q
Describe the process of inspiration?
A
Impulses stimulating contraction are transmitted to the diaphragm via the phrenic
nerve which arises form C3,4 & 5
- The diaphragm contracts causing its dome to move downwards - thereby enlarging the thorax (increasing its volume)
- Simultaneously, activation of the motor neurones in the intercostal nerves to the EXTERNAL intercostal muscles, causes them to contract - resulting in an upward and outward movement of the ribs and a further increase in thoracic volume
- As the thorax expands the intrapleural pressure is being lowered and the transpulmonary pressure is becoming more positive - resulting in lung
expansion since the force acting to expand the lungs (transpulmonary pressure) is becoming greater than that of the elastic recoil exerted by the lungs - The lung expansion results in the alveolar pressure becoming negative
- This results in an inward airflow
- At the end of inspiration, the chest wall is no longer expanding but has yet to start passive recoil, since lung size is not changing and the glottis is open at this point
- alveolar pressure = atmospheric pressure, since the elastic recoil of the lungs has been balanced by the transpulmonary pressure - resulting in no airflow
6
Q
Describe the process of expiration?
A
1At the end of inspiration, the motor neurones to the diaphragm and external intercostal muscles decrease their firing so these muscles can relax - the
diaphragm ascends thereby decreasing thoracic volume
2
As they relax, the lungs and chest walls start to passively collapse due to elastic recoil - this is because the muscle relaxation causes the intrapleural pressure to increase, thereby decreasing the transpulmonary pressure (becomes more negative), this results in the transpulmonary pressure acting to expand the lungs
becoming less than the elastic recoil acting to reduce the lungs eventually resulting in the lungs passively collapsing
3
As the lungs become smaller, air in the alveoli becomes temporarily compressed resulting in an increase in alveolar pressure i.e it becomes more positive and exceeds atmospheric pressure resulting in air flowing outwards
• Thus it can be seen that EXPIRATION AT REST is PASSIVE relying only on the relaxation of the external intercostal muscles and diaphragm and the elastic
recoil of the lungs
7
Q
Describe the process of forced expiration?
A
- On top of the actions mentioned in expiration at rest, the INTERNAL intercostal muscles also contract as do the abdominal muscles
- This results in the ribs moving downwards and inwards - actively decreasing thoracic volume, and the abdominal muscle contraction results in an increase in
intra-abdominal pressure - thereby forcing the relaxed diaphragm further up into the thorax - further decreasing thoracic volume - Resulting in a greater than normal volume of air being expired
8
Q
Which airway has the highest resistance?
A
When air is breathed in or out there is some resistance generated by the airways. The airway with the GREATEST RESISTANCE is the TRACHEA - this is
because although the bronchioles for examples are small, and thus you’d think they’d offer the most resistance, in fact if you add them all up they provide much more surface area meaning they will provide less RESISTANCE than the trachea which has a much smaller surface area than ALL the bronchioles meaning it will provide the MOST RESISTANCE
9
Q
Define Dead Space?
A
Dead space: the volume of air not contributing to ventilation ( anatomically theres is
around 150mls of this and in the alveolar there is around 25mls thus in the lungs in
total there is 175mls of dead space in total)
• Occurs in between the alveoli & capillaries
10
Q
What is the total combined area for gas exchange?
A
the total combined area for gas exchange is 40-100m2
11
Q
How many layers must O2 diffuse through?
A
When O2 diffuses from the alveoli into the pulmonary capillaries & CO2 diffuses
from the pulmonary capillaries into the alveoli the gases must diffuse through 7
layers [we will look at it from O2 perspective i.e. from the alveoli into the capillaries]:
1. Alveolar epithelium
2. Tissue interstitium
3. Capillary endothelium
4. Plasma Layer
5. Red cell membrane
6. Red cell cytoplasm
7. Haemoglobin binding
12
Q
What is ventilation perfusion matching?
A
To be most efficient, the correct proportion of alveolar airflow (ventilation) and capillary blood flow (perfusion) shows be available to each alveolus
13
Q
What is the term for mismatching and what is the consequence?
A
Any mismatching is termed ventilation-perfusion inequality
• The main effect of ventilation-perfusion inequality is that the partial pressure of
oxygen (PO2) is decreased in systemic-arterial blood
14
Q
Can V/Q mismatch occur in a healthy individual?
A
there is naturally some ventilation-perfusion inequality as it is, enough to reduce the arterial PO2 5mmHg - this is due to gravitational effects. One effect of an upright posture is to increase the filling of blood vessels at the bottom of the lung due to gravity, which contributes to the difference in blood-flow distribution in the lung. This concept explains why on average, the PO2 in the alveoli is roughly 5mmHg higher than in the arterial blood
15
Q
How can regional changes in lung compliance, airway resistance, and vascular resistance cause significant ventilation-perfusion inequalities?
A
As a direct consequence of disease, regional changes in lung compliance, airway resistance and vascular resistance can cause significant ventilation-perfusion
inequalities.
The two extremes are:
1. There may be ventilated alveoli but no blood supply at all (known as dead space
or wasted ventilation) due to a blood clot for example
2. There may be adequate blood flow through the areas of the lung but there is no
ventilation (this is termed shunt) due to collapsed alveoli
16
Q
What is the mechanism of Hypoxic Pulmonary Constriction?
A
A decrease in ventilation within a group of alveoli - as a result of a mucous plug blocking the small airways, for example, will lead to a decrease in alveolar PO2 and in the area around it, including the blood vessels
- This decrease in the partial pressure of O2 in the alveoli and nearby blood vessels leads to VASOCONSTRICTION - diverting blood away from the poorly ventilated area
- This effect is unique to the pulmonary arterial vessels (since in systemic circulation the opposite would occur) - it ensures that blood flow is directed away from diseases areas of the lung toward areas that are well-ventilated
17
Q
What is the mechanism of Local Bronchoconstriction?
A
If there is a local decrease in blood flow within a lung region due to, for example, a small blood clot in a pulmonary arteriole.
- The local decrease in blood flow will mean there is less systemic CO2 in the area,resulting in a local decrease of the partial pressure of CO2
- This results in BRONCHOCONSTRICTION which diverts airflow away to areas of the lung with better perfusion
• Both the factors mentioned above greatly improve the efficiency of pulmonary gas exchange - but they are NOT PERFECT even in a healthy lung - there is ALWAYS a small ventilation-perfusion mismatch which leads to the normal alveolar-arterial O2 gradient of about 5mmHg
18
Q
What is PaCO2?
A
Arterial CO2
19
Q
What is PACO2?
A
Alveolar CO2
20
Q
What is PaO2?
A
Arterial O2
21
Q
What is PAO2?
A
Alveolar O2
22
Q
What is PIO2?
A
Pressure of Inspired Oxygen
23
Q
What is V̇A?
A
Alveolar ventilation
24
Q
What is V̇CO2?
A
CO2 production
25
What is the structure of haemoglobin?
Each haemoglobin molecule is a protein made up of four subunits bound together. Each subunit costs of a molecular group known as haem and a polypeptide attached to the haem. The four polypeptides of a haemoglobin molecule are collectively called
globin. Each of the four hemmed groups in a haemoglobin molecule contain one
atom of iron (Fe2+), to which molecular oxygen binds. Thus a SINGLE HAEMOGLOBIN MOLECULE can bind 4 OXYGEN MOLECULES - due to Fe2+ x 4
26
What is the equation for the reaction between 1 O2 and a haem unit?
O2 + Hb ⇄ HbO2
27
What are the two forms of haemoglobin?
Hb (deoxyhaemoglobin) and HbO2 (oxyhaemoglobin)
28
Describe the haemoglobin curve?
curve is sigmoid shaped since because each haemoglobin contains four sub-units,
each subunit can combine with one molecule of oxygen, and the reaction go the four
subunits occur sequentially (i.e. one after the other), with each combination
facilitating the next one
- From the curve it can be seen that at the extent to which oxygen combines with haemoglobin increases very rapidly as the partial pressure of oxygen (PO2) increases from 10 to 60mmHg, so that at a partial pressure of oxygen at 60mmHg approximately 90% OF THE TOTAL HAEMOGLOBIN IS COMBINED WITH OXYGEN the haemoglobin can be said to be 90% saturated at this point
- From this point onwards, a further increase in the partial pressure of oxygen produces only a small increase in oxygen binding - the curve plateau’s after
60mmHg
- This plateau at higher partial O2 pressures is very important. In many situations,including at high altitude & with pulmonary disease, a moderate reduction in
alveolar O2 partial pressure and thus arterial partial pressure. Even if the partial O2 pressure is decreased from the normal value of 100 to 60mmHg, the total
quantity of O2 carried by haemoglobin would decrease by only 10% since haemoglobin saturation is still close to 90% at a partial oxygen pressure of 60mmHg. The plateau provides an EXCELLENT SAFETY FACTOR so that even a significant limitation of lung function still allows almost normal oxygen saturation of haemoglobin
Haemoglobin gives up oxygen in areas of low partial O2 pressure i.e metabolically active tissue where oxygen will diffuse from an area of high concentration to an area of low concentration
29
What is the effect of an increase in temperature and decrease in pH on the oxygen disocciation curve?
An increase in TEMPERATURE and a decrease in pH (or increase in acidity)causes the disassociation curves to shift to the RIGHT - this means that at any given partial O2 pressure, haemoglobin has LESS affinity for oxygen
• Temperature is increased because of the heat produced by tissue metabolism
• pH is decreased/acidity is increased because of the elevated CO2 partial pressure (which enters from the tissues) and the release of metabolically produced acids e.g. lactic acid
• Haemoglobin being exposed to this elevated partial CO2 pressure, H+ concentration & temperatures as it passes through the tissue capillaries has a decreased affinity for oxygen - thus meaning it gives up more oxygen than if the decreased tissue capillary partial O2 pressure was the only operating factor
• The more metabolically active a tissue is, the greater its partial CO2 pressure, H+ concentration and temperature will be. This causes the haemoglobin to release more oxygen during passage through tissue’s capillaries and provides the more active cells with additional oxygen
30
What is the effect of a decrease in temperature and an increase in pH on the oxygen dissociation curve?
Shifts to the left
A shift of the curve to the LEFT (can remember as Left = Locks in O2 more) will have the opposite effect - that is that at any given partial O2 pressure, haemoglobin will have MORE affinity for oxygen
31
What is the effect of carbon monoxide on the oxygen dissociation curve?
Carbon monoxide also influences the oxygen-disassociation curve. CO has a 200 times greater affinity for the oxygen-binding sites on haemoglobin than O2. For this reason it reduces the amount of oxygen that combines with haemoglobin in pulmonary capillaries by competing for sites. It also alters the
haemoglobin molecule itself so it has less of an affinity for O2. This means that CO shifts the oxygen-haemoglobin dissociation curve to the LEFT - thus decreasing the unloading of O2 from haemoglobin in the tissues
32
What is the relationship between partial pressure of arterial CO2 and alveolar ventilation?
The partial pressure of arterial CO2 is inversely related to alveolar ventilation: PaCO2 = kV̇CO2 / V̇A
33
What are the three ways that CO2 is carried in the blood and what are the percentages?
CO2 is carried in the blood in three ways:
1. Bound to haemoglobin - 23% approximately via this reaction:
• CO2 + Hb ⇄ HbCO2
• Forming carbaminohaemoglobin - this reaction is aided by the fact that deoxyhaemoglobin (Hb) formed as blood flows through tissue capillaries has a
greater affinity for CO2 that does oxyhaemoglobin (HbO2)
2. Plasma dissolved CO2 - 10% approximately
3. As HCO3- (bicarbonate) - 60-65% via this reaction
CO2 +H2O ⇄ H2CO3 ⇄ HCO3- + H+
34
What is Dalton's Law?
pressure exerted by each gas in a mixture of gases is independent of the pressure exerted by the other gases. This is because gas molecules are normally so far apart that they do not affect each other. Each gas in a mixture behaves as though no other gases are present, so the total pressure of the mixture is simply the sum of the individual pressure known as partial pressures which are directly proportional to its concentration
35
What is Boyle's Law and what is the equation?
pressure of a fixed amount of gas in a container is inversely proportional to container’s volume
P1V1 = P2V2
36
What is Henry's Law?
amount of gas dissolved in a liquid is proportional to the partial pressure of gas with which the liquid is in equilibrium - at equilibrium the partial pressures of the gas molecules in the liquid and gaseous phases must be identical
37
What is the alveolar gas equation?
PAO2 = PiO2 - PaCO2/R (R= the respiratory exchange ratio)- the ratio between the amount of CO2 produced in metabolism and oxygen used
38
What is the equation for pressure?
Flow x resistance
39
What is the Law of Laplace and what is the equation?
describes the relationship between pressure (P), surface tension(T) and the radius (r) of an alveolus
P = 2T/r
40
What is Lung Compliance?
the change in lung volume caused by a given change in transpulmonary pressure; the greater the lung compliance, the more readily the lungs are expanded
41
What are the determinants of lung compliance?
Elasticity of lung tissues and surface tension of the air-water interfaces of the alveoli
42
What is surface tension and how is it reduced in the alveoli?
At an air-water interface, the attractive forces between the water molecules -
known as surface tension, make the water lining like a stretched balloon that
constantly tends to shrink and resists further stretching
• Thus, the expansion of the lungs, requires energy not only to stretch the
connective tissue of the lung but also to OVERCOME the surface tension of the
water layer lining the alveoli
• In pure water, the surface tension is so great that lung expansion would require
exhausting muscular effort and eventually result in lung collapse
• Luckily, TYPE II PNEUMOCYTES in the alveoli, produce SURFACTANT which markedly REDUCES the cohesive forces between water molecules on the alveolar surface. Thus surfactant lowers the surface tension, which in turn increases lung compliance and makes it EASIER to EXPAND the lungs
• The amount of surfactant tends to decrease when breaths are small and constant.
• A deep breath, which people normally intersperse frequently in their breathing pattern, stretches the type II pneumocytes, which in turn stimulates the secretion of surfactant - this is why patients who have had thoracic or abdominal surgery and are breathing shallowly because of the pain must be urged to take occasional deep breaths
43
What is the normal pH in the body and what is the range?
7.4 (7.35-7.45)
44
What are the three main buffering systems in the body? What is the most important system?
Intracellular and extracellular buffers
The lungs eliminating CO2
renal HCO3- reaborption and H+ elimination
• The most important buffer is the carbonic acid/bicarbonate buffer which works in
tandem with the lungs to compensate for increased carbonic acid production
45
What is the bicarbonate buffer equation?
CO2 +H2O ⇄ H2CO3 ⇄ HCO3- + H+
46
What is the process of respiratory acidosis?
When a person hypoventilates i.e. there is inadequate ventilation of the alveoli meaning CO2 cannot be excreted and expired adequately, the partial pressure of CO2 increases thereby resulting in more carbonic acid being produced and thus an increased H+ concentration in the blood
47
What is the process of respiratory alkalosis?
Conversely hyperventilation would decrease arterial partial CO2 pressure and thus H+ concentration
48
What is the Henderson Hasselbach equation?
pH=6.1* + log10([HCO3-]/[0.03*PCO2])
- * = Dissociation constant for the bicarbonate buffer system
- 0.03*PCO2 = estimate of H2CO3
- 0.03 = the blood CO2 solubility co-efficient
49
What is the location of the neurons primarily involved in the control of breathing?
Control of breathing resides primarily in neurons in the medulla oblongata, the same area of the brain that contains the major cardiovascular control centres
50
What are the two components of the Medullary Respiratory Centre?
Dorsal Respiratory Group (DRG) and the Ventral Respiratory Group (VRG)
51
What is the role of the DRG?
These primarily fire during inspiration and have input to the spinal motor neurons that activate respiratory muscles involved in inspiration - diaphragm and external intercostal muscles
52
What is the role of the VRG?
- The respiratory rhythm generator is located in the pre-Botzinger complex of neurons in the upper part of the VRG
- This rhythm generator appears to be composed of pacemaker cells and a complex neural network that, acting together, set the basal respiratory rate
- The VRG contains expiratory neurons that appear to be most important when large increases in ventilation are required e.g. during strenuous physical activity
- During active expiration, motor neurones activated by the expiratory output of the VRG cause the expiratory muscles to contract
- During quiet breathing the respiratory rhythm generator activates inspiratory neurons in the VRG that depolarise the inspiratory spinal motor neurons, resulting in the inspiratory muscles contracting
• The medullary inspiratory neurons receive a rich synaptic input from neurons
from various areas in the PONS - the part of the brainstem, just above the medulla
53
What is the location of the Apneustic Centre and what is its role?
An area of the lower pons called the apneustic centre is thought to be involved in fine-tuning the output of the inspiratory neurons of the medulla and in continuing to activate inspiratory neurons to inhibit expiration. It can be overridden by the pneumotaxic centre
54
What is the location of the pneumotaxic centre and what is its role?
An area of the upper pons called the pneumotaxic centre regulates and on occasion can override the activity of the apneustic centre. The pneumotaxic centre is also known as the pontine respiratory group and acts to smooth the transition between inspiration and expiration. It is also thought to be involved in switching off inspiratory neurons to prevent hyperinflation thus allowing expiration
55
What receptors are present in the nose, nasopharynx and larynx and what is their response in respiration?
Chemo and mechanoreceptors, some appear to
sense and monitor flow - stimulation of these receptors appears to inhibit the central controller i.e medullary respiratory centre
56
What receptors are present in the pharynx and what is their response in respiration?
has receptors that appear to be activated by swallowing - respiratory activity stops during swallowing thereby protecting against risk of aspiration of food or liquid
57
What are the charactarestics and response of Slowly Adapting Stretch Receptors (SASR's)?
Characteristics:
-Myelinated
- Maintain a persistent or slowly decaying receptor potential during constant
stimulus - initiating action potentials in afferent neutrons for the duration of the
stimulus
- Found in airway smooth muscle
- Activated by lung distension
Response:
High activity inhibits further inspiration, thus beginning expiration
- If inflation is maintained they slowly adapt to low frequency firing
58
What are the characteristics and the response of Rapidly Adapting Stretch Receptors (RASR's)?
Characteristics:
- Myelinated
- Generate a receptor potential and action potentials at the onset of a stimulus but
very quickly cease responding
- Found between airway epithelial cells
- Activated by lung distension and irritants
Response:
- Produce brief burst of activity
- High activity causes bronchoconstriction
- Might be involved in the cough reflex
59
What are the characteristics and response of C Fibres J Receptors?
Characteristics:
- Non-myelinated
- Found either in the capillary walls or the interstitium
-Stimulated by an increase in lung interstitial pressure causes by the collection offluid in the interstitium. Such an increase can occur during the vascular congestion
caused by either occlusion of a pulmonary vessel (pulmonary embolism) or left
ventricular heart failure as well as by strenuous activity in healthy people
Response:
- Activity results in rapid breathing (tachypena), shallow breathing,
bronchoconstriction, cardiovascular depression & a dry cough
- In addition, neural input from J receptors gives rise to sensations of pressure in the
chest and dyspnea - the feeling that breathing is laboured or difficult
60
What is the location of the peripheral chemoreceptors?
Located high in the neck at the bifurcation of the common carotid arteries (quite
close to the carotid sinus) and in the thorax on the arch of the aorta are called the CAROTID BODIES and AORTIC BODIES.
- In both locations, they are quite close to, but distinct from, the arterial baroreceptors and are in intimate contact with the arterial blood
- The carotid bodies, in particular, are strategically located to monitor oxygen supply to the brain
61
What is detected by the peripheral chemoreceptors and what is the mechanism?
- The peripheral chemoreceptors are composed of specialise receptor cells stimulated mainly by a decrease in the arterial partial pressure of oxygen and an increase in the arterial H+ concentration. Type II cells located here - on there detection of hypoxia (low O2 levels) release stored neurotransmitters that stimulate the carotid sinus nerve. These cells provide excitatory synaptic input to the medullary inspiratory neurons
- The carotid body input is the predominant peripheral chemoreceptor involved in the control of respiration
- Peripheral chemoreceptors are not sensitive to small reductions of the arterial partial O2 pressure, it is only when the arterial partial pressure of O2 goes comes close to 60mmHg (where haemoglobin is close to 90% saturated - see oxygen dissociation curve) that the peripheral chemoreceptors begin to really fire and thereby increase ventilation in order to raise the arterial partial O2 pressure. This occurs due to the fact that total oxygen transport of the blood is not really reduced very much until the arterial partial pressure of O2 falls below 60mmHg - thus increased ventilation would not result in much more O2 being added to the blood until that point is reached
- The same occurs with carbon monoxide in the blood, since CO does not effect the amount of O2 that can dissolve in the blood and does not alter the oxygen- diffusion capacity of the lung, the arterial partial O2 pressure is unaltered meaning that no increase in peripheral chemoreceptor output or ventilation occurs
62
What is the location of the central chemoreceptors?
Located in the medulla
63
What is detected by the central chemoreceptors and what is the mechanism?
-Provide excitatory synaptic input to the medullary inspiratory neurons
- They are stimulated by an increase in the H+ concentration of the brains cerebra spinal fluid (CSF) - HOWEVER since the blood-brain barrier is relatively impermeable to H+, changes in H+ in the blood are poorly reflected in the CSF. However, CO2 diffuses readily into the CSF and blood partial CO2 pressure can
influence CSF pH enabling the central chemoreceptors to detect H+ changes
- Very small increases in the arterial partial CO2 pressure causes a marked reflex increase in ventilation - the reflex mechanisms controlling ventilation prevent SMALL increases in arterial partial CO2 pressure to a MUCH GREATER DEGREE than they prevent equivalent decrease in the arterial partial O2 pressure
- Thus, ventilatory drive is extremely sensitive to changes in the arterial partial CO2 pressure of blood entering the brain:
- If there is an increase in the arterial partial CO2 pressure then some of the extra CO2 will diffuse into the CSF, there the CO2 will react with H2O in the CSF as in the reaction above, eventually resulting in more H+ ions enabling the central
chemoreceptors to detect the pH change and thus increase ventilation by stimulating the medullary inspiratory neurons
- NOTE: peripheral chemoreceptors will also detect the increase in the arterial partial CO2 pressure and will send potentials to the medullary inspiratory centre to stimulate ventilation BUT the CENTRAL chemoreceptors account for 70% of the increased ventilation
64
Define the arterial pressure of oxygen?
PaO2 – Partial pressure of oxygen at sea level (160 mmHg in the atmosphere, 21% of standard atmospheric pressure of 760 mmHg) in arterial blood is between 75 mmHg and 100 mmHg and is the measure of oxygen within the arterial blood.
65
Define arterial pressure of CO2?
The partial pressure of arterial carbon dioxide (PCO2) is the measure of carbon dioxide within arterial blood. It often serves as a marker of sufficient alveolar ventilation within the lungs. Generally, under normal physiologic conditions, the value of PCO2 ranges between 35 to 45 mmHg, or 4.7 to 6.0 kPa
66
Define Hypoxia?
Defines as a deficiency of oxygen at the tissue level
- The most common type of hypoxia is hypoxic hypoxia or hypoxemia: in which the
arterial partial O2 pressure is reduced
67
What are the most common causes of hypoxia?
Hypoventilation
Diffusion Impairment
Shunting
Ventilation-Perfusion mismatch
68
Describe how hypoventilation leads to hypoxia?
results in an increased arterial partial CO2 pressure:
- Failure to ventilate the alveoli adequately
- Caused by; muscular weakness (motor neurone disease), obesity & loss of
respiratory drive (e.g. if you prevent the brain from accessing the lungs due to morphine for example)
69
Describe how diffusion impairment leads to hypoxia?
- Results from the thickening of the alveolar membranes or a decrease in their
surface area - causes the blood partial O2 pressure and alveolar partial O2 pressure
to fail to equilibrate
- Caused by; pulmonary oedema (gaseous diffusion issues due to fluid in the lungs),anaemia (blood
diffusion issues) and interstitial fibrosis (between alveolus andcapillaries, connective tissue is thickened)
70
Describe how shunting leads to hypoxia?
- An anatomical abnormality of the cardiovascular system that causes mixed venous
blood to bypass ventilated alveoli in passing from the right side of the heart to the left side e.g. ventricular septal defect (VSD) - Eisenmenger’s Syndrome
- An intrapulmonary defect in which mixed venous blood perfuses unventilated alveoli. Can occur in the bronchial arteries
71
Describe how ventilation-perfusion mismatch leads to hypoxia?
MOST COMMON CAUSE OF HYPOXEMIA:
- Occurs in chronic obstructive lung disease and many other lung disease
- Arterial partial CO2 pressure may be normal or increased, depending on how much
ventilation is reflexively stimulated
- Can be caused by; a pulmonary embolus (blockage of an artery in the lung),asthma, pneumonia & pulmonary oedema
72
What is hypercapnia and what are its causes?
- Carbon dioxide retention and an increased arterial partial CO2 pressure
- Principally caused by HYPOVENTILATION
- Can sometimes be caused by ventilation-perfusion mismatch depending on how much ventilation is reflexively stimulated
73
What are the values and causes of Type 1 Respiratory Failure?
Values:
pO2 (partial O2 pressure) is low
• pCO2 (partial CO2 pressure) is low or normal
• With Type 1 = 1 change = low pO2 then normal/low CO2
Causes:
```
Causes:
• Pulmonary embolism (form of ventilation-perfusion mismatch) most commonly causes Type 1
• Infection
• Pneumonia
• Bronchiectasis
• Congenital
• Cyanotic congenital heart disease
• Neoplasm
• Lymphangitis carcinomatosis
Airway
COPD
Asthma
Vasculature
Pulmonary embolism
Fat embolism
Parenchyma
Pulmonary fibrosis
Pulmonary oedema
Pneumoconiosis
Sarcoidosis
```
74
What are the values and causes of Type 2 Respiratory Failure?
Values:
pO2 is low
• pCO2 is high
• With Type 2 = 2 changes = low pO2 + high pCO2
```
Features:
• Hypoventilation causes Type 2
• Lack of respiratory drive
• (ii) Excess workload
(iii) Bellows failure
```
```
Causes:
• Airway
• COPD
• Asthma
• Laryngeal oedema
• Sleep apnoea syndrome
• Drugs
• Suxamethonium
• Metabolic
• Poisoning
• Overdose
Neurological
Central
Primary hypoventilation
Head and Cervical spine injury
Muscle
Myasthenia
Polyneuropathy
Poliomyelitis
Primary muscle disorders
```
75
What are the clinical features of hypoxia?
```
• Central Cyanosis
• Oral cavity
• May not be obvious in anaemic patients
• Irritability
• Reduced intellectual function
• Reduced consciousness
Convulsions
Coma
Death
```
76
What are the clinical features of hypercapnia?
* Variable patient to patient
* Irritability
* Headache
* Papilloedema
* Warm skin
* Bounding pulse
* Confusion
* Somnolence
* Coma
77
What is the treatment for type 1 respiratory failure?
```
Airway patency
Oxygen delivery
Many differing systems
Increasing FiO2
Primary cause (e.g. antibiotics for pneumonia)
```
78
What is the treament for type 2 respiratory failure?
Airway patency
Oxygen delivery
Primary cause (e.g. antibiotics for pneumonia)
Treatment with O2 may be more difficult
For example; COPD patients rely on hypoxia to
stimulate respiration (they require low percentage oxygen treatment)
* Assisted ventilation
* Invasive
* Non invasive
* Inadequate PaO2 despite increasing FiO2
* Increasing PaCO2
* Patient tiring
79
Define Inspiratory Reserve Volume (IRV)?
Amount of air in excess tidal inspiration that can be inhaled with maximum effort
80
Define Expiratory Reserve Volume (ERV)?
Amount of air in excess tidal expiration that can be exhaled with maximum effort
81
Define Residual Volume (RV)?
Amount of air remaining in the lungs after maximum expiration; keeps alveoli inflated between breaths and mixes with fresh air on next inspiration
82
Define Vital Capacity (VC)?
Amount of air that can be exhaled with maximum effort after maximum inspiration (ERV + TV + IRV); used to assess strength of thoracic muscles as well as pulmonary function
83
Define Functional Residual Capacity (FRC)?
Amount of air remaining in the lungs after a normal tidal expiration (RV + ERV)
84
Define Inspiration Capacity (IC)?
Maximum amount of air that can be inhaled after a normal tidal expiration (TV + IRV)
85
Define Total Lung Capacity (TLC)?
Maximum amount of air the lungs can contain (RV + VC)
86
Define Tidal Volume (TV)?
Amount of air inhaled or exhaled in one breath - 500ml a breath
87
What is FEV1, what is the procedure and what are abnormal values?
Forced expiratory volume in 1 second
In which a person takes a maximal inspiration and then exhales maximally as fast
as possible. The important value is the fraction of the total “forced” vital capacity
expired in 1 second
• Healthy individuals can expire approximately 80% of the vital capacity in one second
It's a good overall assessment of lung health
Procedure:
1. Breathe in to total lung capacity (TVC)
2. Exhale as fast as possible in one second
3. Volume produced is the FEV for 1 second
Abnormal Values:
• The result is compared with the predicted values, if the FEV1 is 80% or greater than
the predicted value = NORMAL
• Thus is the FEV1 is less than 80% of the predicted value = LOW i.e abnormal
88
What is FEV6?
Forced expiratory volume in 6 seconds (graph above is a volume time plot)
Procedure:
1. Breathe in to TVC
2. Exhale as fast as possible for 6 seconds
3. Volume produced is the FEV for 6 seconds
89
What is Forced Vital Capacity (FVC) and what is an abnormal value?
forced vital capacity, the total amount of air forcibly expired
• Less reproducible than FEV1
• The result is compared with the predicted values, if the FVC is 80% or greater than
the predicted value = NORMAL
* Thus is the FVC is less than 80% of the predicted value = LOW i.e abnormal
* A low FVC = airway restriction
90
What is FEV1/FVC ratio and what are abnormal values?
* The proportion of FVC exhaled in the 1st second
* FEV1 is divided by FVC
* If the ratio is below 0.7 = airway obstruction
* If the ratio is high i.e. normal but the FVC is low = airway restriction
• Examples:
1. If measured FEV1 = 1.8 & FVC= 3.3, then the ratio = 1.8/3.3 = 0.55 [low]
- Then look at predicted values: FEV1 = 2.94 & FVC= 3.70 , work out percentages
of predicted values; FEV1 = 1.8/2.94 * 100 = 61% [low] & FVC = 3.3/3.70 * 100 =
89% [normal]
- Thus the ratio is low (below 0.7) and the FEV1 is low & the FVC is normal
Therefore this patient has airway obstruction
2. If measure FEV1 = 1.1 & FVC = 1.2, then the ratio = 1.1/1.2 = 0.92 [normal]
- Then look at predicted values: FEV1 = 3.6 & FVC = 4.55, work out percentages of
predicted values; FEV1 = 1.1/3.6 * 100 = 31% [low] & FVC = 1.2/4.55 * 100 = 26%
[low]
- Thus the ratio is normal (above 0.7) and the FEV1 is low & the FVC is low
- Therefore this patient has airway restriction
91
What are the features of pulmonary circulation vascular physiology?
```
Vessel wall is thin
• Minor muscularisation
• No need for redistribution
- Right Atrium: 5 mmHg
- Right Ventricle: 25 mmHg
- Pulmonary Artery: 25/8 mmHg
```
92
What are the features of systemic circulation vascular physiology?
```
• Vessel wall is thick
• Significant muscularisation
• Redistribution is required
• Pressure is much higher than in the pulmonary circulation
- Left Atrium: 5 mmHg
- Left Ventricle: 120 mmHg
- Aorta: 120/80 mmHg
```
93
What are the four issues of the lung associated with ageing?
1. Delayed response to hypercapnia (abnormally high arterial partial CO2 pressure) and hypoxia - thus at increased vulnerability to ventilatory failure
2. FEV and FVC decreases thus FEV1/FVC decreases thus their normal spirometry
reading may indicate obstructive - may mask or mimic respiratory symptoms and
disease
3. Impaired Gas Exchange
4. Decreased Immune System Function
94
What are the reasons for imparied gas exchange in the ageing lungs?
- Due to changes in the shape of the thorax
- Costal cartilage becomes stiffer - harder to breathe
- Respiratory muscle decreases in mass - less effective
- Reduction in type IIA muscle fibres (fast-fatigue resistant) - thus get more tired
when breathing = breathe less/less efficiently
- Denervation of muscle fibres - results in less contraction, thus less potent inspiration
- Loss of elastic recoil in lungs
- Elastin fibres in alveoli and respiratory bronchiole degenerate and rupture
- Ventilation-perfusion (V/Q) mismatch increases
- Reduction in alveolar surface area
- Reduced lung capillary and blood flow
- Oxygen saturation of haemoglobin declines with normal ageing. Not important at rest. Effects are seen in times of demand e.g. exercise or ill health
95
What are the causes of reduced immune function in the ageing lungs?
- Glandular epithelia cells decrease thus less protective mucus
- Decrease sputum clearance
- Less effective mucociliary system
96
What is PiO2?
Pressure of inspired oxygen
100 kPa x 0.21=0.21 21KPa at sea level
97
What is FiO2?
Fraction of inspired oxygen
0.21 never change
98
How is PaCO2 calculated?
Directly proportional to 1/alveolar ventilation
99
What is pressure of inspired gas?
Patm(atmospheric pressure) x Fraction of inspired gas
100
What is the alveolar gas equation?
PAO2 = PiO2 - PaCO2/R
- R = respiratory quotient (CO2 produces/O2 consumed)
- A = alveolar
- a = arterial
- R = 0.8 with a normal diet
- R = 1 with a primarily carbohydrate diet
- R = closer to 0.7 with fat rich diets
101
How can we calculate PaO2 with the alveolar gas equation?
PaO2 = PAO2 - A-aDO2
- = 12.5 -1 = 11.5 KPa
- A = alveolar
- a = arterial
- A-aD = arterial-alveolar difference - tends to be 1KPa due to ventilation-perfusion
(V/Q) mismatch, even in healthy people due to gravity which increases the
filling of blood in vessels in the bottom of lung, resulting in ventilation-perfusion
inequalities
102
What are the normal blood gases and pH at sea level?
PaO2 = 10.5 - 13.5 KPa
- PaCO2 = 4.5 - 6.0 KPa
- pH = 7.36 - 7.44
103
What happens to pressure as altitude increases? What happens to the PiO2?
As altitude rises = pressure decreases, but
not a linear relationship
• Need to go to 5,000 metres to half barometric
pressure
• FiO2 remains CONSTANT AT APPROX 0.21
• PiO2 FALLS with altitude
104
What is the normal response in the body to high altitude?
- Hypoxia leads to hyperventilation (normally at 10,000 feet) results in; increased minute ventilation, lowers PaCO2, alkalosis initially & tachycardia (heart rate
rises)
- Alkalosis is compensated for by renal bicarbonate excretion
105
What is Acute Mountain Sickness and what are the symptoms?
Caused by a recent ascent to over 2500m
- Lake Louise score greater than 3
- Must have a headache and one other symptom e.g. lethargy, shortness of breath
- Can ONLY be treated with descent
- Younger people at risk
106
What is High Altitude Pulmonary Oedema and what are the symptoms?
- Affects unacclimated individuals
- Acute mountain sickness, COUGH + SHORTNESS OF BREATH
- Causes by a rapid ascent above 8000ft (2438m)
- Risk is less if you sleep below 6000ft (1829m)
- Treat with; oxygen, descent
107
What is the change in pressure in atm for every 10m descended in diving?
1 atmosphere
108
What is Boyle's Law?
At a constant temperature the absolute pressure of a fixed amount of gas is inversely proportional to its volume:
P1V1 = P2V2
109
Worked example of using Boyle's Law
Example using boyle’s law: The total lung
capacity in a 23 yr old female diver is 8 litres at
the surface. What will this volume be at 160m of
seawater during breath hold diving?
- P1V1 = P2V2
- Atmospheric pressure at the surface = 1atm
- Atmospheric pressure at 160m = 17 (since every 10m = 1atm, and don't forget to
count the 1atm at the surface!)
- Thus: 8 x 1 = 17 x V2
- 8/17 = V2
V2 = 0.470 litres
- 470 mls
110
What is Henry's Law and how does it relate to diving?
The amount of a gas dissolved in a liquid at a given temperature is directly proportional to the partial pressure of the gas
- Thus proportionally more gas dissolves in the tissues at depth
- So if you ascend at a rate that exceeds the body’s capacity to clear this excess gas
- inert bubbles may form in tissues resulting in decompression illness
111
What is the diving reflex?
• Diving reflex with FREE DIVING; aponea (stop breathing), bradycardia (slow heart rate) & peripheral vasoconstriction
112
What is hypersensitivity?
Refers to diseases in which immune responses to the environmental antigens cause inflammation and damage to the body itself. More prevalent in adaptive immunity
113
In the Gell and Coombs Classification, how many types of hypersensitivity are there?
4
114
What are the four types of hypersensitivity?
Type 1- IgE
Type 2-(IgG bound to cell surface antigens/ IgM)
Type 3- Immune complexes, activation of complement/IgG
Type 4-Cell Mediated Delayed Type Hypersensitivity (DTH)
115
Describe Type 1 Hypersensitivity and give examples?
Speed: Allergic, Acute
Description:
Immunological memory to something causes an allergic response
• Also called IgE-mediated hypersensitivity
• Immediate hypersensitivity
• IgE Antibody-mediated
Atopy:
- Inherited tendency to exaggerated IgE response to antigen
- Affects 25% of the population but less than half develop atopic disease
- Examples include; hay fever, eczema & asthma
- Can diagnose atopy with a skin prick test
• In type 1 - initial exposure to the antigen leads to some antibody synthesis and the
production of B memory cells (mediate active immunity). Upon exposure, the antigen
elicits a more powerful antibody response. In type 1 though, particular antigens that elicit type 1 reactions stimulate, in those with atopy, the production of type IgE antibodies. Production of IgE requires the participation of a particular type of T helper cell that are activated by the allergens presented by B cells. These activated T helper cells trigger the mast cell to secrete inflammatory mediators, including histamine & chemokines (cytokines that have chemoattractant actions) which then initiate a local inflammatory response. NOTE: if the mast cells secrete very large amounts of mediators and they enter circulation, then systemic symptoms may result and cause severe hypotension, vasodilation & bronchoconstriction (causing mucous hypersecretion secretion) - ANAPHYLAXIS
Examples:
acute anaphylaxis, hay fever
116
Describe Type 2 Hypersensitivity and give examples?
Speed: Immediate and Acute
Description:
* Occurs when antibodies IgM or IgG bind to cell-surface-associated antigens
* Leads to tissue injury or altered receptor function
Examples:
* transfusion reactions
* autoimmune disease
* Example of the hypersensitivity is haemolytic disease of the newborn
117
Describe Type 3 Hypersensitivity and give examples?
Speed: Fairly Quick
Description:
• Antibody IgG binds to a soluble antigen thereby forming a circulatory immune
complex
• Little lumps of target and antibody are deposited in the skin, lung, kidneys etc.
• Activates immune response and local inflammation results in tissue damage
Examples:
```
• SLE
• Post-streptococcal GN
• Granulatoma
• Farmers lung - they inhale mouldy hay, results in a type 3 reaction, resulting in fever, cough, flu-like illness, breathlessness and crackles all caused by a local
inflammatory response in the lungs
• Malt-workers lung
• Mushroom workers lung
• Pigeon fanciers lung
```
118
Describe type 4 hypersensitivity and give examples?
Speed: Delayed
Description:
• Independent of antibodies
• Mediated by helper T cells & macrophages
• Due to a pronounced secretion of cytokines by T helper cells activated by an
antigen in the area. These cytokines act as inflammatory mediators and also
activate macrophages to secrete their potent mediators
• Since it takes several days to develop this hypersensitive is also referred to as
delayed hypersensitivity
Examples:
* TB
* Seen in granulomatous diseases such as sarcoidosis
* Contact dermatitis from poison ivy
119
Describe the features of the parasympathetic system in the airways?
Neurotransmitter: Acetylcholine (Ach)
- Innervates lung via vagus
- Innervates vasculature, glands & airways in the lungs
- Intrinsic tone of airways is governed by the parasympathetic system:
• Ach interacts with muscarinic (M3) cholinergic receptors on the muscle to provide a general level of intrinsic muscle tone
• Too much parasympathetic activation i.e. too much Ach results in bronchoCONSTRICTION
- NOTE: ACh is released by both the sympathetic and
parasympathetic but in the lungs; ACh is primarily released by the parasympathetic
120
Describe the features of the sympathetic system in the airways?
Neurotransmitter: Noradrenaline (NAd)
- Innervates lung via the sympathetic trunk
- Innervates vasculature & glands - does not directly innervate the airways
Indirect influence of the sympathetic system on airways tone:
• Sympathetic activation causes NAd to be released to the adrenal glands and can result in the release of adrenaline (from adrenal medulla) which in turn binds to beta-2-adrenoreceptors on muscles of the airways and subsequently results in bronchoDILATION - thus this is the indirect effect of the sympathetic system
on the airways
121
What are the features of cholinergic receptors?
* Neurons that release ACh are called cholinergic neurons
| * Neurons associated with ACh system degenerate in people with Alzheimer’s disease
122
What are the features of nicotinic receptors?
Respond to ACh as well as nicotine, hence the name
- Stimulated by both sympathetic and parasympathetic - but mainly parasympathetic
- Found in post-ganglionic neurons
- Found in neuro-muscular junction
- Contains a ligand-gated channel that is permeable to both Na+ and K+ ions, but
since Na+ has a larger electrochemical driving force the net effect of opening these
channels is depolarisation
123
What are the features of muscarinic receptors?
- Parasympathetic
- Many types: M1, M2, M3 (lungs), M4, M5
- M3 receptors plays an important role in the airways:
1. Acetyl Choline (ACh) binds to M3 receptor
2. Receptor couples with Gq protein
3. Gq protein activates phospholipase C (PLC)
4. Phospholipase C (PLC) catalyses the breakdown of a plasma membrane
phospholipid to diacylglycerol (DAG) and inositol triphosphate (IP3)
5. DAG acts as a second messenger and activates a family of proteins known a
protein kinase C (PKC)
6. IP3 binds to ligand-gated Ca2+ receptors located on the endoplasmic reticulum in
the bronchial cells, which open when IP3 is bound to them, resulting in Ca2+
release which will then stimulate BRONCHOCONSTRICTION
• M3 receptor is found in the lungs - when acetylcholine binds to it =
BRONCHOCONSTRICTION
124
What are the features of adrenergic receptors?
Neurons that release NAd (noradrenaline) are called adrenergic
Alpha Adrenergic Receptor:
- Two types; alpha-1 & alpha-2
- Alpha-1: Acts postsynaptically to either stimulate/inhibit the activity of different
types of K+ channels
- Alpha-2: Acts presynaptically to inhibit noradrenaline release
Beta Adrenergic Receptors:
- Act via stimulatory G proteins to increase cAMP in the postsynaptic cell
- Three types; beta-1 (heart), beta-2 (lung) & beta-3 (adipose)
- Beta-2 receptor:
• G couple protein receptor:
1. Adrenaline or noradrenaline binds to receptor
2. Receptor couples with Gs protein
3. Gs protein activates Adenyl Cyclase (AC)
4. Adenyl Cyclase then catalyses the conversion of cytosolic ATP to cyclic 3’,5’-
adenosine monophosphate or cyclic AMP (cAMP)
5. cAMP then acts as a second messenger then diffuses in the lung resulting in a
decrease in calcium concentrations as well as other effect e.g. activates protein
kinase A (PKA) - eventually resulting in BRONCHODILATION
• Beta-2-adrenoreceptor is found in the lungs - when noradrenaline OR adrenaline
binds to it= BRONCHODILATION
125
What are the two types of receptor ligand, what are their characteristics, and what are examples?
Type:
Agonist
Characteristics:
a compound that binds to a receptor and activates it, demonstrates both
affinity and efficacy
Examples:
- Muscarine binds to muscarinic acetyl choline receptor (mAChR)
- Nicotine binds to nicotinic acetyl choline receptor (nAChR)
Type:
Antagonist
Characteristics:
a compound that blocks the effect of an agonist by competing with a
chemical messenger for its binding site - but does not activate signalling normally -
thus blocking its action, has affinity but zero efficacy
Examples:
- Atropine binds to muscarinic acetyl choline receptor (mAChR) - reverses effect of
acetyl choline e.g. use to help people poisoned with sarine (from homeland)
126
What two factors determine whether a ligand acts as an agonist or an antagonist?
Affinity:
• The degree to which a particular messenger binds to its receptor is determined by the
affinity of the receptor for the messenger
• A receptor with high affinity will bind at lower concentrations of a messenger that
will a receptor of low affinity
• Affinity is a property shown by both antagonists and agonists
Efficacy:
* Describes how well a ligand activates a receptor
* High efficacy agonist: results in a large change in receptor shape when it binds
* Low efficacy agonist: results in a small change in receptor shape when it binds
* Antagonist: results in no conformational change to receptor shape when it binds
127
What are the two types of medications used to treat inflammation based respiratory conditions, what are their effects and what are examples?
Type of treatment:Beta agonist
What receptor does it act on: Beta-2 adrenoreceptor
Neurotransmitter involved: Noradrenaline (Nad)
Role: Increase bronchodilation (sympathetic)
Short acting (around 4 hours): salbutamol & terbutaline
Long acting (about 12 hours): salmeterol & formoterol
Type of treatment:Muscarinic Antagonists
What receptor does it act on: Muscarinic 3 receptor
Neurotransmitter involved: Acetyl Choline (ACh)
Role: Blocks bronchoconstriction (parasymphathetic)
Short acting (around 4 hours): ipratropium
Long acting (about 12 hours): tiotropium
128
In Non-Immune Host Mechanisms, what are the 4 types of lung defence?
barrier function, leucocyte recruitment, cytokine and growth factors
129
What is respiratory epithelium and how does it participate in non-immune host mechanism?
ciliated pseudostratified columnar epithelium:
- Serve to moisten and protect the airways
- Also functions as a barrier to potential pathogens and foreign particles
- Prevents infection and tissue injury by action of the mucociliary escalator
130
What are surface defence mechanisms in non-immune host mechanisms?
- The various skin glands, salivary glands and lacrimal (tear glands) secrete
antimicrobial chemicals such as;
• Antibodies
• Lysozyme - enzyme which destroys bacterial cell walls
• Lactoferrin- iron-binding protein which prevents bacteria from obtaining the iron they
require to function properly
- The respiratory epithelium and upper gastrointestinal tracts secrete mucus;
• This mucus contains antibodies
• Its also very sticky - meaning particles adhere to it and are reverted from entering
the blood - they are either swept by ciliary action (escalator mechanism) up into the
pharynx and then swallowed, or are phagocytosed by macrophages in the various
linings
- The respiratory epithelia also produce other chemical barriers:
• anti-fungal peptides
• anti-microbial peptides
- There is also a huge amount of non-pathogenic bacterial flora right down into the
deepest parts of the lungs - which helps keep the immune system primed for
pathogens
131
What physical defence mechanisms are present in non-immune host mechanisms?
- Coughing:
• A cough is an explosive expiration that provides a normal protective mechanism
for clearing the tracheobronchial tree of secretions and foreign material
• A cough may be initiated either voluntarily or reflexively
• The receptors for the cough reflex are in the larynx, trachea and bronchi
• When the receptors are stimulating the medullary inspiratory neurones reflexively
cause a deep inspiration (about 2.5 litres)
• The epiglottis is closes and the vocal cords shut tightly to entrap air within the
lung
• The abdominal muscles contract forcefully, pushing against the diaphragm
• The internal intercostal muscles also contract forcefully
• Pressure in the lungs rises to 100mmHg or more
• Markedly positive intrathoracic pressure causes narrowing of the trachea
• Vocal cords and epiglottis suddenly open widely
• The large pressure differential between the airways and the atmosphere coupled
with tracheal narrowing produces rapid flow rates through the trachea
• Air is expelled at velocities ranging from 75-100 mph
• In this manner, particles & secretions are are moved form smaller to larger airways
and aspiration of materials into the lungs is also prevented
• NOTE: alcohol inhibits the cough reflex - explaining partially why alcoholics are
susceptible to choking and pneumonia
132
What are the features and purposes of mucus?
• Mucus secretion and clearance are extremely important for airway integrity and
pulmonary defence
• Airway mucus is a viscoelastic gel containing water,
carbohydrate, proteins and lipids
• It is a secretory product of the goblet cells of the
airway surface epithelium and submucosal glands
• Mucous protects the epithelium from foreign material
and fluid loss
• Its transported from the lower respiratory tract into the
pharynx by air flow and mucociliary clearance/
escalator
• The mucociliary escalator constantly brings up
mucus by cilia beating in directional waves up the airway
• It protects the epithelium by being in physical contact with it
• Consists of a superficial gel/mucous layer and a liquid/periciliary (SURFACTANT)
fluid layer that bathes the epithelia cilia
133
What is the process of epithelial injury?
• Infections caused by viruses often target specific epithelial cells, whereas bacteria
are less specific
• Following an injury to the airway epithelium, the epithelium can carry out a full repair
i.e regenerate itself
• This is due to the fact that epithelium exhibits a level of functional plasticity
• When this process goes wrong, it can result in pulmonary disease
134
What is pulmonary disease?
• Commonest cause of death in the developing world
• Is almost entirely environmental rather than genetic
• Most are characterised by epithelia defects and thus sufferers have impaired host
defence
• Abnormal epithelial response to injury underpin many obstructive lung disease
• One example of where this occurs is severe asthma (others include COPD and CF)
• Asthma:
- Extrinsic: response to inhaled antigen
- Intrinsic: non-immune mechanisms (cold or exercise)
- Bronchial asthma: a chronic inflammatory disorder characterised by hyperactive
airways leading to episodic reversible bronchoconstriction - constriction reduces
the amount of air that can reach the peripheral lungs
- Bronchoconstriction results in excessive mucus production which can result in the
formation of mucus plugs (arise from secretion of the epithelia and the submucosal
glands)
- Mucus plugs can completely obstruct airways and are often fatal
135
What is meant by humoral?
things that are in the blood/plasma NOT cells
136
What are the cells of the immune system?
Neutrophil: they are phagocytes (they eat stuff), some are antigen presenting cells
Macrophage: they are phagocytes (they eat stuff), some are antigen presenting cells
Lymphocytes: they make antibodies, kill diseased cells and decide what sort of antibodies to make
Immunoglobulins (Humoral): antibodies
Complement (Humoral): (formation of the membrane attack complex)
Surfactant Proteins: -
Cytokines:proteins that allow leukocytes and tissue cells to talk to each other
137
What are the features of innate immunity?
• Immediate
• Does not require prior exposure to recognise that something is wrong
• Mainly involves phagocytosis of bacteria and rapid responses to viruses
- INFLAMMATION:
• Local response to infection or injury
• Main functions:
- Destroy or inactive foreign invaders
- Set the stage for tissue repair
• Key mediators are the cells that function as phagocytes - the most important of which
being neutrophils, macrophages & dendritic cells
138
What is the process of innate immunity?
Bacteria are introduced to a wound
Chemical mediators cause vasodilation & capillary permeability;
chemoattractants recruit neutrophils to area
Diapedesis (passage of leukocytes out of the blood and into the surrounding
tissue) results in neutrophils entering tissue where they engulf and phagocytose
bacteria
Capillaries return to normal as neutrophils continue to clear the infection
139
Describe acute inflammation in the lungs?
• Initiated in the tissues, typically by specialist tissue resident macrophages
including:
- Kupffer cells (liver)
- Alveolar macrophages (lung)
- Histiocytes (skin,bone)
• These cells initiate a cascade of events that result in inflammation
• They respond to pathogens or to tissue by recognising:
- PAMPs (Pathogen-Associated Molecular Patterns)
- DAMPs (Damage-Associated Molecular Patterns
• These cells recognise new pathogens that we have never seen before by using
Pattern recognition receptors (PRRs) which are part of the innate immunity which recognise common antigens on bacteria - one major receptor is the Toll-Like Receptor
• Toll-Like Receptor (TLR):
- Expressed in the plasma & endosomal membranes of macrophages and dendritic cells amongst others
- These proteins recognise and bind to PAMPs these include; viral & bacterial nucleic acids and a protein found in the flagellum of bacteria
- When binding of a TLR occurs on the plasma membrane of a macrophage for example, second messengers are generated within the immune cell, which in turn leads to the secretion of inflammatory mediators such as IL-1, IL-12 & TNF-a.
These in turn stimulate the activity of immune cells involved in the innate immune response such as NEUTROPHILS and some involved in the adaptive immune response
140
Describe alveolar macrophages?
- Alveolar macrophages comprise
93% of the pulmonary
macrophages
- Functionally similar to macrophages; phagocytosis,
extracellular killing via secretion of toxic chemicals, process and present antigens to T helper cells
and secrete cytokines involved in inflammation, activation and differentiation of helper T cells,
and systematic response to infection or injury
- Long-lived and arise from monocytes (enter tissues and transform into macrophages - produced in the bone marrow)
141
Describe monocytes?
* High phagocytic capacity (bacteria and apoptotic cells)
* Intermediate ATP generation
* High susceptibility to apoptosis (programmed cell death)
142
Describe tissue macrophages?
• High-intermediate phagocytic capacity (lower, percentage, higher number of ingested
particles)
• High ATP generation
• Low susceptibility to apoptosis
- Functions of the alveolar macrophage:
• Resident phagocyte of the lungs
• Co-ordinates the inflammatory response (cytokine production)
• Induction & clearance of apoptotic cells
• An alveolar macrophage is meant to destroy bacteria in the alveoli swiftly and with
little help i.e. without inducing a massive immune response - occurs daily
• However if needs be, the macrophage can illicit a huge response by calling in neutrophils - resulting in pneumonia
143
Describe neutrophils?
• 70% of all white blood cells are neutrophils
• 80 million made a minute
• Turnover 100 million a day
• Related to monocytes and macrophages
• Produced in the bone marrow
• Contain granules - which are released to help combat infection in a process
called DEGRANULATION:
- PRIMARY GRANULES CONTAIN:
• Myeloperoxidase (enzyme used to carry out anti-microbial activity)
• Elastase - enzyme that breaks down elastin in lungs - enables neutrophil to migrate
through lung to get to pathogen
• Cathepsins & defensins (anti-bacterial proteins)
- SECONDARY GRANULES CONTAIN:
• Receptors
• Lysozyme - enzyme that breaks down bacterial cell walls
• Collagenase - enzyme that breaks down collagen, allows neutrophils to penetrate
hard to reach collagenised areas - collagen particles produced by the break down
of collagen are chemotactic - cause more neutrophils to come to area - self
amplifying mechanism
144
Describe the neutrophil function of Identifying the threat through receptors?
- Recognises bacterial structure e.g. cell walls, lipids, peptides
- Has receptors to detect host mediators (signal of attack); cytokines, lipids
- Recognises host opsonins (any substance that binds a microbe to a phagocyte
and promote phagocytosis) e.g. FcR (immunoglobulin) & CR3 (complement -plasma protein that is recognised by neutrophils targeting the pathogen for
destruction)
145
Describe the neutrophil function of activation?
- Neutrophils are often in the switched off state since these are very dangerous cells
to always have on
- Via stimulus response coupling
- Signal transduction pathways involving calcium,protein kinases, phospholipase & G proteins
146
Describe the neutrophil function of adhesion?
- In the first stage, the neutrophil is loosely tethered to the endothelial cells of a blood vessel by selectins (adhesion molecule) - process is known as margination, occurs as the neutrophil rolls along the vessel surface. This process exposes the neutrophil to chemoattractants being released in the injured area
- These chemoattractants act on the neutrophil to induce the rapid appearance of
integrins (another class of adhesion molecule) on the neutrophils plasma membrane, these integrin molecules bind tightly to their matching molecules on the surface of endothelial cells - meaning the neutrophils collect along the site of injury rather than being washed away with the flowing blood
147
Describe the neutrophil function of migration/chemotaxis?
- A narrow projection of the neutrophil is inserted into the space between two endothelial cells, and the entire neutrophil squeezes through the endothelia wall and into the interstitial fluid. In this way, huge numbers of neutrophils migrate into the
inflamed area - this process is known as diapedesis
- Once in the interstitial fluid, neutrophils fallow a chemotactic gradient and migrate towards the site of tissue damage (chemotaxis). This occurs because pathogen-stimulated innate immune cells release chemoattractants - resulting in neutrophils
moving toward the pathogens that entered into the injured area
148
Describe the neutrophil function of phagocytosis?
- The initial step is contact between the surfaces of the phagocyte and microbe. One of the major triggers for phagocytosis during this contact is the interaction of
phagocyte receptors with certain carbohydrates or lipid in the microbial cell wall
- Sometimes contact is not enough to trigger engulfing especially with bacteria that are surround by a thick gelatinous capsule
- Instead, chemical factors produced by the body can bind the phagocyte tightly to the microbe and thus enhance phagocytosis - any substance that does this is known as an opsonin
- When the phagocyte engulfs the microbe it is trapped in a internal sac called a phagosome isolating the microbe within the neutrophil
149
Describe the neutrophil function of bacterial killing?
- The phagosome membrane then makes contact with one go the neutrophils
lysosomes (filled with hydrolytic enzymes) and the membranes of both of them
fuse and the combined vesicle is now called a phagolysosome
- Within the phagolysosome, the lysosome enzymes break down and destroy the
microbe, other enzymes from the phagolysosome membrane are produced such as
the reactive oxygen species hydrogen peroxide (generated by the membrane
complex NADPH oxidase) and nitric oxide all of which are extremely destructive to
the microbe - hydrogen peroxide can then be converted to a hydroxyl radical to
destroy the pathogen
150
What are the 6 functions of neutrophils?
1. Identifying the threat through receptors
2. Activation
3. Adhesion
4. Migration/chemotaxis
5. Phagocytosis
6. Bacterial Killing
151
What is the difference between necrosis and apoptosis?
Necrosis: cells swell, then lyse and reactive oxygen species and other enzymes are released which can cause damage to the surrounding tissues - results in
inflammation and phagocytosis of necrosed cell
Apoptosis: more controlled, cell is turned off and packaged to then be phagocytosed by neutrophils with no surrounding tissue damage
152
What is the difference between innate immunity and adaptive immunity?
• Two systems intimately interrelated
• Initial responses to pathogens often innate
• Later responses adaptive
• Previously encountered pathogens are tackled more robustly
- Antigen MUST be present to be recognised e.g. by dendritic cells or Macrophages
153
What cell types are involved in adaptive immunity?
T Cells, B Cells, Macrophages
154
Describe T cells and their role in adaptive immunity?
- TYPE OF LYMPHOCYTE
- Involved in cell-mediate immunity and the direct killing of cells
- Made in bone marrow, BUT mature in thymus
- Cytotoxic T cell - the attack cell, following activation they travel to the location of their target, bind to them via antigens on these targets, and directly kill these targets via secreted chemicals
- T Helper cell - assist in the activation and function of B cells, macrophages & cytotoxic T cells:
• They require CLASS II MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) proteins to function. Only macrophages, B cells and dendrite cells express class II MHC proteins and thus can function as antigen presenting cells (APC’s) for T helper cells
• First they combine with the antigen and then undergo activation - at which point they migrate to the site of B cell activation, B cells that have bound antigen present it to the activated helper cells. Then antigen-specific T helper cells make direct contact with B cell, and the communication via surface receptors along with cytokine secretion, INDUCES B cell activation
• In cytotoxic T cell activation, the T helper cell assists activation indirectly via other cells e.g. dendritic cells
155
Describe B cells and their role in adaptive immunity?
- TYPE OF LYMPHOCYTE
- Involved in antibody production (activated which causes them to differentiate into
plasma cells which secrete antibodies - they travel all over the body to reach
antigens identical to those that stimulated their production)
- Made in bone marrow mature but are stored in secondary lymphoid organs e.g.
lymph nodes etc
- There are 5 types of antibody; IgA, IgD, IgE (made to things we’re allergic to), IgG
[MOST ABUNDANT] & IgM (made at the beginning of infection)
- Each antibody recognises a specific epitope (portion of antigen that is recognised by
a specific antibody)
- When activated by a T helper cell it becomes a plasma cell (which produces the
antibodies) which lives a few days only
156
Describe macrophages and their role in adaptive immunity?
important in orchestrating healing
- Functions of the adaptive immune response:
• The recognition of specific ‘non-self’ antigens in the presence of ‘self’ antigens,
during the process of antigen presentation
• Generation of responses tailored to eliminate specific pathogens or pathogen-infected cells
• Development of immunological memory, with each pathogen remembered by signature antibodies & T-cell receptors
- Immunological memory also rapid immunological response on subsequent exposure & is the basis of immunisation
157
Describe antigen presenting to T cells?
- T cells can bind antigen only when the antigen appears on the plasma membrane of
a host cell complexed with major histocompatibility complex (MHC) proteins. Cells bearing these MHC proteins function as antigen-presenting cells (APCs)
158
What are the 8 functions of the respiratory system?
1. Filtration
2. Humidification
3. Warming
4. Olfaction and Taste
5. Gas Transport
6. Speech
7. Protection against infection
8. Gas Exchange
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Does the lung have a function in the foetus?
No
160
What respiratory tract structures come from endoderm?
epithelia lining of trachea, larynx, bronchi & alveoli
161
What respiratory tract structures come from the splanchnic mesoderm?
cartilages, muscle,connective tissue of tract & visceral pleura
162
What are the different stages of lung development?
Pseudoglandular-5-16 weeks
Canalicular- 16-26 weeks
Terminal Sac- 26 week to birth(Type 1 and 2)
Alveolar- 8mo to childhood
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What happens in the pseudoglandular phase?
Branching to form terminal bronchioles
164
What happens in the canalicular phase?
Each terminal bronchiole divides into > 2 respiratory bronchioles, each which divide into 3-6 ducts
165
What happens in the Terminal Sac Phase?
Terminal Sacs (primitive alveoli form) and capillaries closely touch. Only 1/6 adult number alveoli at birth
166
What happens in the Alveolar Phase?
Alveoli mature, more respiratory bronchioles and alveoli
167
What are the features of foetal circulation?
• Lungs are of no use to foetus
• PaO2 = 3.2 KPa (equivalent to 31,000 feet)
• Shunting of blood from Right to Left: due to high vascular resistance in the lungs
meaning the pressure is higher in the right of the heart (supplies the lungs) than the
left, thus blood will shunt through to the left via the foramen ovale
- Tissue resistance (fluid filled)
- Low systemic resistance (placenta)
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What is the hypoxia response in the systemic circulation in the foetus?
• Purpose: deliver O2 to hypoxic tissue
• Hypoxia/acidosis/CO2 are vasodilators - arteries dilate so more oxygen can be
provided to tissues
• Thus when O2 levels are high there is vasoconstriction as not as much O2 is
required
• Thus is systemic circulation O2 is a vasoCONSTRICTOR
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What is the hypoxia response in the pulmonary circulation in the foetus?
- Purpose: pick-up oxygen from oxygenated lung
- Hypoxia/acidosis are vasoconstrictors - since blood will be shunted away to alveoli
with better ventilation etc.
- Oxygen is a vasoDILATOR since dilation will mean MORE oxygen can be picked up
170
What happens in the lungs at birth?
1. Fluid in lungs is squeezed out by birth process
2. Adrenaline released due to stress = increase in surfactant release
3. Air is inhaled
4. Oxygen vasoDILATES pulmonary arteries
5. Umbilical arteries and ductus arteriosus constrict becoming the medial umbilical
ligaments & ligamentum arteriousum respectively
- At birth pulmonary artery pressure goes down exponentially and aortic pressure
goes up - since lung pressure goes down and systemic blood pressure goes up,
blood moves into the lungs via diffusion to be oxygenated
171
What is surfactant? What can go wrong?
Produced by type 2 pneumocytes from 34 WEEKS GESTATION, there is a dramatic increase in production in the 2 WEEKS PRIOR TO BIRTH
- In premature babies they are surfactant deficient can result in respiratory distress syndrome of the newborn:
• Type 2 pneumocytes are too immature to function adequately
• Since low surfactant decreases lung compliance means that the baby can only inspire by the most strenuous of effort which may ultimately result in complete exhaustion, inability to breather, lung collapse and death
