Suzie Rayner

Respiratory System 1 – Introduction

• To list the main functions of the respiratory system that will be covered in
greater detail in the rest of the course
o Gas exchange
o Host defence
o Metabolism of endogenous and exogenous molecules
o Repair
o Vocalisation

Respiratory System 2 –
Basic structure of the respiratory system
• Sketch and name the cellular layers separating alveolar air from blood.

• The two basement membranes enclose an

interstitial space (containing pulmonary
capillaries, elastin and collagen)

• Alveolar-capillary membrane is <5μm

• Define alveoli, bronchioles, bronchi, trachea, larynx, pharynx, and nasal

cavities.
Alveoli: microscopic spaces lines by very thin simple squamous epithelium through
which oxygen and carbon dioxide exchange occurs with blood in the alveolar capillaries
Bronchioles: further branching from bronchi, microscopic tubes, initially surrounded by
smooth muscle but ending as respiratory bronchioles
Bronchi: branches visible to naked eye, initial branch from trachea to primary bronchus
at the sternal angle (costal cartilage 2),
Trachea: short tube from the larynx into the upper chest, held open by cartilage
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Larynx: a valve that allows air into the lower airways but excludes liquids and solids
(Adam’s apple)
Pharynx: tube immediately posterior to mouth and nasal cavity, opens posteriorly to
oesophagus and anteriorly to larynx and then trachea.
Nasal cavities: mucosal lined cavity on either side of nasal septum, nearly triangular
cross section, with smooth medial and inferior walls but an elaborate lateral wall where
respiratory epithelium covers 3 scroll like plates of bone (Conchae)

• Outline how the respiratory tract is protected against drying, cold and inhaled
particles.
• Inspired air passes through the conchae becoming warmed and humidified on
route
• This protects the lower parts of the respiratory tract from cold shock and drying
• This process cools nasal cavities, so during expiration the expelled air is cooled
and water is retrieved by condensation
• Nasal mucus and hairs exclude airborne particles
• During exercise, nasal resistance to air flow becomes too great and open
mouthed breathing takes over (less protection)

• Explain how the alveoli and airways resist collapse.

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• Trachea and bronchi are held open by cartilage

• The bronchi are held open by cartilage horseshoes and plates
• Bronchiolar and alveolar surface tension are reduced by surfactant (wetting
agent that lower interfacial tension)

• Describe and sketch the organisation of the chest using the terms chest wall,
diaphragm, mediastinum, pleural cavities, pleura, and lungs.
[Covered in anatomy in detail]

• Mediastinum lies between pleural cavities, sternum and vertebrae (containing

heart, oesophagus, trachea, great vessels)
• Diaphragm is attached to costal margin but bulges into thoracic cavity, it is a
sheet like muscle
• Two layers of pleura cover the lungs (visceral on the lung surface and parietal
on the costal surface)
• Lungs have 3 surfaces: costal (facing ribs), mediastinal (in contact with
mediastinum) and diaphragmatic (in contact with diaphragm)

• Explain the roles of chest wall muscles, diaphragm, chest wall skeleton, pleural
cavities, pleura and lungs in breathing in and out.
[Covered in Anatomy in detail]
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• Diaphragm is the main muscle involved in breathing. Contraction of diaphragm

pulls the domed centre down and increases height of pleural cavities.
• During inspiration, the external intercostal muscles contract, causing the ribs to
move upwards and outwards creating a larger thoracic cavity (increases both
antero-posteriorly and transversely)
• The increase in size of thoracic cavity lowers the pressure causing air to rush
into the lungs, causing them to expand
• Lower part of each lung expands downwards to occupy much of costo-
diaphragmatic recess
• Breathing out (normally) is passive

• Outline the blood circulation through the lungs making correct use of the terms
double circulation, pulmonary circuit, right atrium, tricuspid valve, right
ventricle, pulmonary valve, pulmonary trunk, pulmonary arteries, arterioles,
alveolar capillaries, venules, pulmonary veins, left atrium.
• Body has double circulation; one for deoxygenated blood (pulmonary) and
one for oxygenated (systemic)
• In the pulmonary circuit, deoxygenated blood enters the right atrium via the
inferior and superior vena cava.
• Atrial systole forces the blood into the right ventricle (through the tricuspid
valve)
• Ventricular systole then ejects the blood into the pulmonary trunk (through the
pulmonary valve) which branches into pulmonary arteries.
• The pulmonary arteries branch further into arterioles and capillaries within
each lung which carries blood close to alveolar so that gas exchange can occur
• The oxygenated blood returns to the heart via venules and pulmonary veins
which enter the heart at the left atrium.

Respiratory system 3 –
Ventilation and gas exchange
• Distinguish between alveolar and pulmonary ventilation.

Ventilation is (usually) measured using a spirometer.

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Spirometry is used to diagnose repiratory disease and monitoring to assess various

things.

Where spirometer cannot be used – in the case of residual volume (RV) and functional
residual capacity (FRV) – gas dilution technique or body plethysmography is used.

Pulmonary ventilation:
• a.k.a Minute ventilation
• Minute ventilation = volume of air entering lungs/min
• Healthy: 6-7.5L/min (12-15 breaths/min)

Alveolar ventilation:
• Fresh inspired air available for gas exchange
• Volume of gas entering the respiratory zone (i.e. minute ventilation – volume
remaining in anatomical dead space)
• 150ml remains in anatomical dead space per breath
• Therefore, alveolar ventilation of a healthy person: (500-150)x no. of breaths
• Heathy: 5250ml/min

Alveolar ventilation determines levels of O2 and CO2 in alveolar gas.

Other factors that influence this are:
• Rate of consumption of O2
• Rate of production of CO2
• Hb content of blood
• Hb affinity for O2
• Atmospheric pressure for O2

• Define the common lung volumes and describe how they alter in restrictive and
obstructive disease

litres
Maximal inspiration
8
IRV 3.0 L Vital capacity
VC 4.5 L

Tidal volume
Total lung capacity
VT 0.5 L
TLC 6.0 L

Functional
ERV 1.5 L
residual capacity
FRC 3.0 L Maximal expiration

Residual volume
RV 1.5 L
0
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Functional residual capacity (FRC): lung volume at the end of quiet expiration
Residual volume (RV): lung volume at end of forced expiration
Inspiratory reserve volume (IRV): maximum amount of air that can be inhaled after
normal inspiration
Expiratory reserve volume (ERV): maximum amount of air that can be expelled after
normal expiration
Tidal volume (VT): volume of air breathed in or out during normal respiration
Total lung capacity (TLC): when taking maximum inspiration
Vital capacity (VC): amount of air that can be forced out of the lungs after maximal
inspiration (IRV+VT+ERV = VC)

Lung Volume Normal Clinical relevance

Functional residual capacity
Residual volume
Inspiratory reserve volume
Expiratory reserve volume
Tidal volume
Total lung capacity
Vital capacity
Value
3L • Maintain distal lung patency
• critical value called closing
volume/capacity
1.5L • Can increase in lung disease
• When increased may alter
respiration ‘mechanics’
3L • Required in cough and during
exercise
1.5L
1.5L Adequate VT to clear carbon dioxide and
maintain oxygenation
6L
4.5L • Critical value (1L) used to measure
if patients can maintain
spontaneous ventilation

Alterations due to disease:

Obstructive: asthma, COPD (chronic obstructive pulmonary disease), CF

Restrictive: Ankylosing spondylitis, Lung fibrosis, motor neurone disease

• Reduced oxygenation
• Poor clearance of carbon dioxide
• V/Q mismatch (ventilation and perfusion)
• Increased work of breathing
• Breathlessness
• Reduced exercise tolerance

• Define anatomical and physiological dead space and give approximate

volumes for both in a typical healthy adult
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Anatomical dead space: with each tidal volume, 150ml remain in conducting zone up to
terminal bronchus (i.e. not gas exchange region)

Alveolar dead space:

• Inspiratory gas unable to participate in gas exchange due to insufficient blood
supply
• In healthy individual, almost 0.
• In disease affected by pulmonary embolism, and ventilation of non-vascular air
spaces

Physiological dead space:

• sum of all parts of tidal volume that do not participate in gas exchange
• [alveolar dead space + anatomical dead space]

[N.B. In normal healthy adults, anatomical and physiological dead spaces are the
SAME]

• Describe the effect of increased breathing frequency compared with increased

depth of breathing on alveolar ventilation

• Increased depth of breathing increases alveolar ventilation more than increased

frequency of breath.

Hypoventilation: CO2 level is above that of normal

• Can be localized a lobe or area [Infection]
• Can be scattered throughout lung fields [COPD, asthma]
• Generalised [pain, reduced respiratory drive/consciousness]
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Causes drop in pH, respiratory acidosis

Hyperventilation: CO2 level is below that of normal [N.B. quick breathing]

• Anxiety/fear
• Metabolic disease
• Airway obstruction
• Parenchymal lung disease
• Altitude

Causes increase in pH, respiratory alkalosis

• Define Fick’s law of diffusion

Rate of transfer of gas through a sheet of tissue is proportional to:

• tissue area
• difference between gas’s partial pressures (amount of gas dissolved in the
plasma) on either side of tissue
• diffusion constant (solubility of gas in tissue?)
Inversely proportional to:
• tissue thickness

[N.B. assuming standard barometric pressure of 100 kPa, pO2 = 21kPa, pCO2 =
0.04kPa (same as percentage in air)]

Therefore diffusion is dependent on: [logical]

• concentration/pressure gradient
• gas solubility
• thickness of alveolar membrane (0.5-1μm)
• surface area of alveolar membrane
• ventilation and perfusion

Ventilation: amount of air reaching lungs

Perfusion: amount of blood reaching lungs

CO2 is more soluble than O2 as it is a smaller molecule (therefore has rapid diffusion
even though small gradient)

• Relate Fick’s law of diffusion to gas exchange in health and disease

In respiratory disease
• O2 is primarily affected as less soluble.
• If tissue is thickened (due to inflammation, infection, fibrosis), the rate of
diffusion slows – lead to hypoxia
• Reduced surface area impairs gas exchange (insufficient)
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• Ventilation and perfusion (V/Q) ratio can be mismatched during disease

Respiratory System 4 – Lung Cell Biology

• Know the structure of the mucosa (epithelium + underlying matrix) from the
large conducting airways through to the alveoli.
• Know the cell biology and function of the mucociliary escalator in normal lung
defence and against inhaled toxins and micro-organisms.

The epithelium:
• Form a continuous barrier, isolating external environment from host
• Produce secretions to facilitate clearance (via mucociliary escalator), protect
underlying cells and maintain reduced surface tension
• Metabolises foreign and host-derived compounds
• Releases mediators
• Triggers lung repair processes

Goblet cells - in Large, central, small airways:

• 20% epithelial cells
• Synthesise and secrete mucus
• Mucus is complex, very ‘thin’ sol phase overlays cells, thick gel phase at air
interface
Mucus contains:
Component Role
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Mucus proteins, proteoglycans and Gives mucus viscoelasticity

glycosaminoglycans – released from
goblet cells and seromucouse glands
Serum-derived proteins (albumin, α 1- Combats microorganism and phagocyte
antitrypsin – a.k.a α 1-proteinase inhibitor proteases
which inhibits polymorphonuclear
neutrophil proteases)
Antiproteases – synthesised by epithelial Combats microorganism and phagocyte
cells (secretory leucoprotease inhibitor) proteases
Antioxidants from the blood and Combats inhaled oxidants (cigarette smoke,
synthesised by epithelial cells and ozone).
phagocytes (uric acid and ascorbic acid
Also counteracts excessive oxidants
from blood, gluthathione from cells)
released by activated phagocytes

In smokers:
• Number of goblet cells at least doubles
• Secretions increase and are more viscoelastic
• Harbours microorganisms, greater chance of infection

Ciliated cells - in large, central, small airways

• Normally around 80% of epithelial cells
• Beat metasynchronously (‘field of corn’)
• Tips of cilia in sol phase of mucus push mucus towards epiglottis → swallowed
ore expectorated
In smokers:
• Ciliated cells are severely depleted in smokers with bronchitis
• Reduced mucus clearance, more infections
• Ciliated cells extend into bronchioles of smokers

• Know the role of Clara cells (non-ciliated secretory epithelial cells) and
alveolar type II cells in lung defence and repair.

Clara cells - in large, central, small airways, bronchi and bronchioles:

• Non ciliated, secretory epithelial cells
• Increase proportionally distally (i.e. more as you get further into lungs)
• Major role in xenobiotic metabolism – metabolism of foreign compounds
• Make and release high levels of antiproteases
• Synthesis and secrete lysosyme
• Contain phase I and II enzymes:
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Enzyme Example Role

• Designed to metabolise
Phase I Cytochrome P450 oxidases
foreign compounds into a
enzymes
format that enables phase
II enzymes to react and
neutralize the toxic agent
• However, also often
activate a precarcinogen
to a carcinogen
• Benzo(a)pyrene (BP) is a
precarcinogen in a
particular tar phase of
cigarettes.
• Cytochrome P450
(CYPIA1) oxidises BP to
BPDE which is a
carcinogen.
• Smokers with lung
cancer have
polymorphism of
CYPIA1 that results in
extensive metabolism.
• Enables conjugation of
Phase II Glutathione-S-transferase
BPDE to a small
enzymes
molecule that neutralizes
its activity
• Some people are null to
glutathione-s-transferase,
therefore cannot
neutralize BPDE,
therefore more likely to
get lung cancer if they
smoke.

Alveolar type II epithelial cells (a.k.a type II pneumocytes) – found in alveoli:

• Synthesise and secrete the phospholipid-rich surface active material
(pulmonary surfactant) that prevents lung collapse on expiration. Also has
immunological functions
• Precursor of alveolar epithelial type I cells, divide and differentiate to replace
damaged type I cells
• Synthesise and secrete antiproteases

• Know the role of the alveolar macrophage and polymorphonuclear neutrophil

in normal lung and after inhalation of cigarette smoke, particles, microbes,
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noxious gases etc.

Alveolar macrophages – found throughout but enriched in lower respiratory tract:
• 90% of total phagocytic cells in normal lung (5-10x increase in smoker)
• Important scavenging cells (remove debris and microorganisms)
• Signal to blood/lymphatic system to sequester other inflammatory cells to lungs
during infection or toxic inhalation
• Synthesise and secrete proteases (digests debris, attack organic material)
• Generate oxidants during phagocytosis and on activation to kill infecting
organisms
• Generate antioxidants to neutralize oxidative molecules inhaled or generated
• Contains enzymes to metabolise toxicants

Polymorphonuclear neutrophils – found throughout airways:

• 5% of lower respiratory tract phagocytes (5-10x increase in smoker and
proportionally)
• Higher proportion in upper airways – 30% of phagocytes (up to 70% in
smokers)
• Store high levels of potent proteases in granules, released on activation (high
levels of released proteases in smokers)
• Release very potent oxidative molecules (hydroxyl anions) during activation

• Know the role of the interstitial cells in connective tissue synthesis (brief).
?
• Know what pathology causes obstructive lung disease, especially the role of
uncontrolled inflammation, abnormal tissue repair and mucous production
(tutorial).

COPD (Chronic obstructive pulmonary disease)

• Affects 15-20% smokers
• Mixture of diseases, bronchitis, small airway disease and emphysema
• May exist together or separately
• Many years to develop and become clinically important

Chronic bronchitis:
• large/central airway affected
• Copious mucus production (3 months-year)
• Airway obstructed by mucus and thickened mucosal cell layer

Small airway disease:

• Small airways become blocked/obstructed due to mucus secretion and stenosis
of airway wall due to fibrosis
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Emphysema:
• destruction of the respiratory tissue by proteolytic enzymes
• Leads to loss of connective tissue scaffold, basement membrane and normal
cell organisation
• Loss of surface area and elastic recoil
• Loss of vascular tissue
• Gas exchange is severely compromised
• 10% of smokers affected.

Respiratory System 5 – Lung Development

• To understand the continuum of lung growth and development from conception to
adulthood and the factors that interfere with normal development.

• Tracheal bud from foregut at 4-5 weeks gestation

• Bronchial branching completed by 16 weeks gestation
• Pulmonary artery branching follows bronchial branching
• Alveolar development continues until 8-10years old.
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Lung embryogenesis:
• Different tissues develop at different rates
• Bronchial buds are supplied by systemic vessels
• Systemic vessels regress as pulmonary artery takes over principle supply
• Bronchial artery development takes place independently
• Malformation is caused by timing of insult, not nature

Influences on lung development:

• Hox gene
• Transcription factors
• Autocrine and Paracrine interactions
• Peptide growth factors
• Thoracic cage volume
• Lung liquid positive pressure
• Amniotic fluid volume
• Maternal nutrition

• To understand how congenital lung defects arise.

• To be able to summarise the morphological and/or cellular events associated with

the phases of intrauterine lung development.
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• To understand the early life origins of susceptibility to lung disease.

• To summarise the main aspects of lung growth and the evolution of lung function in
the postnatal period.

• To be able to give a brief account of the changes in the lungs and circulation that
occur at birth to permit air breathing.
• To briefly describe the changes that occur at birth that facilitate the transition to
air breathing. Comment particularly on the role and fate of lung liquid and the
importance of pulmonary surfactant in stabilising breathing.
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At Birth:
• Massive CNS stimulation
• Low pressure placental circulation is cut, causing rise in systemic pressure
• Lung aeration causing fall in pulmonary artery pressure
• Lung aeration causes rise in pO2 and fall in pCO2

Day 1:
• Pulmonary vaso-dilatation with blood flow increased x5
• Reset chemo-receptors and respiratory centres
• Aeration of lungs with high positive expiratory pressure
• Lung volume rises to optimum and airway resistance falls within first 2 hours
• Lung compliance rise takes at least 24 hours
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Respiratory system 6 – Airways function

• Describe the main functions of the airways

• Conduct O2 to alveoli
• Conduct CO2 out of lung [Gas exchange]

Gas exchange is facilitated by:

• Mechanical stability (cartilage)
• Control of calibre
• Protection and cleansing

• Describe the structure of the principal cells of the airways (including epithelial
cells, smooth muscle cells, submucosal glands, inflammatory cells)
• Draw a diagram of an airway showing the relative location of the cells
• Relate the location of the cells to their function
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Category Airway cell type

Lining Ciliated, intermediate, brush, basal
Contractile Smooth muscle (airways, vasculature)
Secretory Goblet, mucous, serous
Connective Fibroblast, interstitial cell (elastin,
collagen, cartilage)
Neuroendocrine Nerves, ganglia, neuroendocrine cells,
neuroepithelial bodies
Vascular Endothelial, pericyte, plasma cell (and
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smooth muscle)
Immune Mast cell, dendritic cell, lymphocyte,
eosinophil, macrophage, neutrophil

Human airway epithelium:

• Made up of goblet cells and ciliated cells
• Goblet cells contain mucin granules
• Ciliated cells contain many mitochondria

Airway submucosal glands:

• Made up of two cell types: mucous and serous acini
• Mucous cells secrete mucins
• Serous cells secrete antibacterials
• Glands also secrete salt and water

• Describe the main functions of the airway cells

• Relate the functions of the airway cells to the overall functions of the airways

Epithelial cell functions:

• Secretion of mucins, salt, water
• Mucus movement
• Physical barrier
• Production of inflammatory and regulatory mediators (NO, CO, Chemokine,
Cytokines, Proteases, prostaglandins)

Ciliary structure:
• 9 + 2 arrangements of microtubules
• Metachronal rhythm (beats out of sync, thus moving
mucus in one direction instead of backwards and
forwards)

Airway smooth muscle functions:

• Structure
• Tone
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• Secretion of mediators, cytokines, chemokines

• During inflammation, smooth muscle cell hypertrophy occurs, increased
proliferation and more secretion.

• Describe the humoral control of the function of the airway cells

Tracheo-bronchial circulation:
• 1-5% of cardiac output
• High blood flow
• Bronchial arteries arise from various places
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• Contributes to warming and humidification of inspired air

• Clears inflammatory mediators and inhaled drugs
• Provides airway tissue and lumen with inflammatory cells
• Supplies airway tissue with proteinaceous plasma

Types of humoral control:

Regulatory and inflammatory mediators:

• Histamine
• Arachidonic acid metabolites (e.g. prostaglandins, leukotrienes)
• Cytokines
• Chemokines

Reactive gas species

Proteinases

• Describe the neuronal control of the function of the airway cells

3 types of nerve:

Parasympathetic – cholinergic – Ach

Sympathetic – adrenergic – adrenaline and noradrenaline
Sensory

Cholinergic – principle motor control of airway (constriction)

Cholinergic nerves → ACh onto muscarinic receptors on:
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o Blood vessels
o Smooth muscle cells
o Submucosal glands

There are little/no adrenergic nerves – rely on adrenal gland

• Briefly relate changes in control mechanisms to the pathophysiology of

respiratory diseases
• Briefly outline the altered functions of airway cells to the pathophysiology of
respiratory diseases

Respiratory diseases with loss of airway control: OBSTRUCTIVE – asthma, COPD,

CF

Prevalence
Asthma – 5% of population
COPD – 4th cause of death in UK/USA
CF – 1:2000 Caucasians

Asthma:
• Increased airway responsiveness to a variety of stimuli, resulting in airway
inflammation and obstruction
• Airway obstruction varies over short periods of time, reversible
• Dyspnea, wheezing, coughing
• Bronchoconstriction: airway wall is thrown into folds, mucus plug in lumen

Respiratory system 7 –
Control of breathing – awake
• Give five examples of respiratory or non-respiratory functions achieved by
control of respiratory muscle activity

• Metabolic homeostasis
• Communicate (speech)
• Facilitate social activities (singing, playing instrument)
• Express emotions
• Posture
• Defecation
• Reflexes (cough, sneeze, yawn)

• Identify neuronal groups in the brainstem that make up the automatic reflex
controller, and structures in higher brain areas (suprapontine) that drive
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behavioural (non-automatic) control of breathing.

• Distinguish the primary purpose of the automatic reflex controller (regulate

gas exchange for metabolic homeostasis) and the behavioural controller
(other needs such as speech)

Two separable controllers in brain:

Autonomic bulbopontine (reflex) controller – brainstem – regulates gas exchange for
metabolic homeostasis

Behavioural suprapontine controller – widely distributed – other needs such as speech

Parts of Behavioural suprapontine controller:

• Willful control (complete cessation to 20x increase) – allows precision, can be

learned, competes for control of respiratory muscles.

• Emotional drives – involuntary psychological influences, secondary to

perception of discomfort, also allows for music perception/athletic
entrainment.

• Wakefulness drive – Tonic excitatory drive when awake, inhibitory drive also
exists

• Explain automatic respiratory rhythm generation in terms of a network of

interconnected neurones with characteristic discharge patterns.
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• Basic respiratory rhythm is controlled by groups of neurons in the brain stem

(pons + medulla)

Rhythm generation:
• Neural network interactions – synaptic interaction between groups of neurons,
resulting in rhythmic bursting activity
• Pacemaker properties – Pre-Botzinger complex (brainstem)
• Locate sources of sensory input to the respiratory control system (central and
peripheral chemoreceptors, lungs, airways and chest wall)

Peripheral chemoreceptor input:

• Carotid bodies ( detect pH, pCO2, hypoxia)
• Aortic arch ( pCO2, hypoxia)

Central chemoreceptor input:

• Surface of medulla (detects pCO2, NOT pH or hypoxia)

Mechanoreceptor inputs:

• Lungs
o Slowly adapting pulmonary stretch receptors (SARs)
o Rapidly adapting pulmonary stretch receptors (RARs)
o J receptors
o Irritant receptors

• Chest Wall
o Joint receptors
o Golgi tendon organs
o Muscle spindles

Sensory input from lungs, airway and chest

wall:
• Nose – Trigeminal (V)
• Pharynx – Glossopharyngeal (IX),
Vagus (X)
• Larynx – Vagus (X)
• Lungs – Vagus (X)
• Chest wall – Spinal nerves

[N.B. all cranial except for chest wall]

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• Describe the ventilatory response to increased arterial PCO2, decreased

arterial PO2, and moderate exercise

Increased PaCO2: increased lung ventilation in proportion to CO2 level

Decreased PaO2: lung ventilation only increases when the O2 level has become quite low
(see graph)

• Respiration rate increases to remove CO2 and tidal volume increases to increase
O2.
• CO2 is detected by central chemoreceptors and O2 by peripheral (carotid
bodies)

Moderate exercise – has a rapid increase in

ventilation over first minute, rate then
slows but ventilation still increases until it
plateaus.

• Define breathlessness as ‘perception’ of respiratory discomfort. State 2 other

terms commonly used for ‘breathlessness’ (‘Dyspnoea’ and ‘Short of
breath’)

Breathlessness: subjective feeling of respiratory discomfort.

Clinical signs of Dyspnoea: Tachypnoea, ‘pursed lip’ breathing, cyanosis, hyperinflation

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Breathlessness – Short of Breath – Dyspnoea

Breathlessness occurs due to mismatch in signals to brain – too many informing of actual
breathing, not enough informing of need to breathe.

Role of Breathlessness:
• No direct role
• Indirectly elicits behaviour to move respiratory system from danger (seek
medical attention, swim to surface, stop exercising)
• Involved in learning breathing response to exercise
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• Appreciate the emotional impact and effect on quality of life of dyspnoea

• Leads to poor quality of life
• Frightening
• Unpleasant feeling
• Overtakes pain in end stages of cancer
• Feeling of impending suffocation

Progress in human investigation:

• Direct stimulation of exposed cortex
• Electrical stimulation
• Transcranial magnetic stimulation
• Brain Imaging
• Neurological patients

Congenital central hypoventilation syndrome (CCHS): lesion of the medulla,

automatic reflex controller affected, therefore only behavioural controller working
Locked in syndrome: lesion of corticospinal pathway (ventral pons), no voluntary motor
control except blinking

Respiratory system 8 – The pulmonary circulation

• Compare the systemic and pulmonary circulations with respect to (i) the structure
of the arteries and arterioles (ii) the mean arterial blood pressure and (iii) the
overall resistance to blood flow.

Role of pulmonary circulation:

• Gas exchange
• Filtering small emboli (fat, blood, air) from the circulation
• Metabolism of vasoactive substances (Angiotensin II, serotonin, noradrenaline,
prostaglandins, leukotrienes removal)- controls vasoconstriction/dilation

Structure of arteries and
arterioles
Structure of capillaries
Mean arterial BP
Systemic
Thicker walls, abundant
smooth muscle
Network structure
Higher – greater distance
for blood to travel
Pulmonary
Thinner walls, less smooth
muscle, large capacity
Very thin walls, mesh
provides thin sheet of blood
Lower

120/80 normal 25/8 normal

Overall resistance to blood Higher Lower
flow
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• Explain how differences in the arterial blood pressures of the two circulations
influence the structure of the two ventricles of the heart.
Higher blood pressure needed in systemic circulation as blood needs to be pumped to
whole body, therefore thicker muscle needed to provide higher pressure in L ventricle.

• Describe and explain the relative difference in blood flow to the bases and apices
of the lungs in a standing human.

• Low blood flow to top of the

lungs, higher towards base –
due to gravity
• Peak blood flow is just
above base as base of lung is
compressed by abdominal
viscera and so cannot get
optimum blood flow.

Blood flow depends on balance of forces on thin-walled collapsible capillaries:

• Held open by intravascular pressure
• Collapsed by alveolar pressure

Zone 1: alveolar pressure >

vascular – causes collapse

Zone 2:
arterial >alveolar<venous –
collapses at distal end (venous)
but can be easily recruited by
increased venous pressure

Zone 3: alveolar<vascular –
remain open.

• Explain, with reference to the pulmonary circulation, the meaning of the terms
vascular recruitment and hypoxic vasoconstriction

Pulmonary circulation can accommodate increased CO2 and filtration – has spare
capacity.
To increase the capacity – recruit (more vessels) or distend (bigger vessels)

Capillary recruitment and distension → fall in pulmonary vascular resistance

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Hypoxic vasoconstriction: mechanism of diversion.

• If alveolar tension falls → active vasoconstriction of pulmonary arteries to
<1000μm → diverts blood flow to aerated regions of lung.
[Active vasoconstriction occurs due to intravascular oxygen sensing potentially O2
mediated free radicals, oxygen-sensitive K+, other ion channels and mitochondria.]

• In absence of
recruitment/distension
mechanisms both lines would
be straight.
• Lines are not horizontal →
indicates mechanisms
preventing increase in PAP if
cardiac output increase is not
perfect
• PAP is always higher in
hypoxic condition due to
hypoxic vasoconstriction
• Isolated lungs indicate hypoxic vasoconstriction is intrinsic mechanism of lung.

• Explain the importance of hypoxic vasoconstriction in the foetus.

• In fetus, pulmonary resistance is higher than systemic; therefore blood flows

from R → L.
• When lungs expand after birth, pressure in pulmonary vessels drops which
reverses flow and closes foramen ovale.
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Fetal development:
• Vascular system develops as ventral and dorsal aortas, right dorsal aorta
regresses leaving the L dorsal aorta.
• 1st, 2nd and 5th brachial arteries regress. 4th becomes aorta and right subclavian
artery. 6th remains as ductus arteriosum until after birth.

Hypoxic vasoconstriction is
important in fetus as it maintains low
blood flow to lungs (higher blood
flow to placenta?)

• Give one advantage and one disadvantage of hypoxic vasoconstriction in an adult

suffering from chronic lung disease
Advantages: Reduces blood flow to areas that will have poor gas exchange
Disadvantage: Vasoconstriction causes increases vascular resistance → pulmonary
hypertension

• Give two reasons why lung disease may lead to pulmonary hypertension. Explain
what is meant by “cor pulmonale”.
Causes of pulmonary hypertension:
• Arterial hypertension
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o primary defect in pulmonary arteries

o Collagen/vascular disease, drugs, congenital heart disease, HIV
• Vascular hypertension
o primary cardiac defect
o L sided atrial, ventricular or valvular disease
• Due to chronic thrombotic/embolic disease
• Miscellaneous disorders

Cor Pulmonale: When heart failure develops in the setting of pulmonary hypertension
associated with respiratory disorders/hypoxia.

• Explain what is meant by pulmonary oedema. Identify 3 pathophysiological

mechanisms that may lead to this state

Pulmonary oedema: fluid accumulation in the lungs

Effects:
• Impaired gas exchange
• Reduced lung compliance
• Increased pulmonary venous pressure

Leads to:
• Increased hydrostatic pressure - high venous pressure
o L heart failure
o Mitral stenosis
• Decreased plasma colloid pressure – reduced plasma proteins
o Starvation
o Abnormal leakage from kidney or gut
• Increased capillary permeability – endothelial cell damage
o Adult respiratory distress syndrome

Clinical symptoms:
• terrified patient
• severe breathlessness
• pink frothy sputum
• crackles on auscultation

• Explain the term “pulmonary embolism” and state the typical site of origin of
such emboli. Describe the consequences of a large embolus with respect to i) the
right side of the heart and the pulmonary circulation, ii) the viability of the lung
tissue and iii) the implications for gas exchange

Pulmonary embolism: blockage of pulmonary artery.

Typically emboli originate in deep veins of calf.
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Leads to:
• RV failure and circulatory collapse
• Increased R heart pressures
• Decreased gas exchange
• Lung infections (rare)
• Normal filtration – unless chronic where pulmonary hypertension develops

• Appreciate, in the context of the pulmonary circulation, the concept of shunting.

Identify the potential deleterious effects of an increased pulmonary shunt

Pulmonary shunt: bypass the alveoli, therefore blood not oxygenated.

[Hypoxic vasoconstriction is not perfect, therefore some blood passes to non-ventilated
areas – constitutes a shunt]

Effects of shunt
Decreased gas exchange as less oxygen → cyanosis, hypoxaemia
R to L shunts
Decreased filtering of small embolis → paradoxical emboli and strokes
Decreased metabolism of vasoactive substances

Respiratory system 9 – Lung Cancer

• Explain the basic pathogenesis of lung cancer.
Causative factors – Tobacco, Radon, Asbestos
Multistep theory of tumour development – arise as consequence of accumulation of
mutations of genes which regulate cell proliferation, invasion, angiogenesis and
senescence.
Squamous cell carcinoma: squamous metaplasia → Dysplasia → carcinoma-in-situ are
precursors (specific genes mutate at specific stages)
Adenocarcinoma: atypical adenomatous hyperplasia is precursor
No precursor yet known for small cell
• Describe the link between cigarette smoking and the incidence of lung
cancer.
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3rd most common cause of death in UK

• Describe the different local and systemic complications of lung tumours.

• Explain what is meant by a paraneoplastic syndrome with examples.
Bronchogenic carcinoma:
Local effects:
• Bronchial obstruction
• Impaired drainage of bronchus
• Invasion of local structures – SVC(leading to venous congestion, dusky head
and arms), oesophagus, chest wall
• Extension through pleura and pericardium
• Diffuse lymphatic spread within lung
Systemic effects:
• Metastasis – brain, bone, skin, liver
• Paraneoplastic syndromes (see below)
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Paraneoplastic syndromes – systemic effect of tumour due to tumour cells abnormally

expressing factors (hormones) – not normally expressed by tissue from which tumour
arose.
Examples:
• Antidiuretic hormone – hyponatraemia (drop in sodium)
• Adrenocorticotrophic hormone – Cushing’s syndrome
• Parathyroid hormone-related peptides – Hypercalcaemia
• Calcitonin – Hypocalcaemia
• Gonadotrophin – Gynecomastia
• Serotonin – Carcinoid syndrome

• Describe the main histological types of lung cancer, their different biological
behaviour, and the significance this has for prognosis and treatment.
Small cell lung cancer
o 20-25% of all lung carcinomas
o Usually arise centrally
o Strong association with smoking
o Nests of small round cells, little cytoplasm, dense core granules
o Most aggressive, metastasise early and widely

Non small cell lung cancer:

• Squamous carcinoma
o 25-40% pulmonary carcinoma
o Close association with smoking
o More often centrally arising from bronchial epithelium
o Local spreads, metastases late
Evidence of squamous differentiation:
keritinisation, intercellular prickles (desmosomes)
• Adenocarcinoma
o Proliferation of atypical cells
o Lining the alveolar walls, eventually becoming invasive
o 25-40% pulmonary carcinoma
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o Most common lung carcinoma in female and non-smokers

o Usually arise peripherally
o Gland or papilla formation, mucin production
• Undifferentiated

Prognosis:
Small cell carcinoma
Untreated: 2-4 month survival
Current therapy: 10-20 months
70% of patients present with extensive
disease
Chemo/chemoradiotherapy more often
used than surgery
Non small cell carcinoma
Stage 1: 60% 5 year survival
Stage 4: 5% 5 year survival
20-30% have resectable tumours, no
metastases
Surgery more often than chemo

Small cell advances at a much higher rate than non small cell cancers.
Treatment:
Small cell –
• Highly responsive to chemotherapy and radiotherapy
• Combination chemotherapy including cisplatin and etoposide (or
cyclophosphoamide, doxorubicin, vincristine)

Non-small cell –
• Surgery (Stage 1, 2, resectable 3)
• In unresectable stage 3 , multi-modality treatment may offer better survival
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• 3 cycles of chemotherapy (in unresectable) with sequential or concomitant

radiotherapy

• Explain how the different sites and spread of the initial cancer in the lung
can influence the chance of resection.
• Complete or partial resection (pulmonectomy) is possible in early peripheral
tumours and where there is no metastasis
• Most commonly metastasizes to lymph nodes, brain, bones, liver – inoperable
and untreatable
• 1/5 of all cases are resectable

• Summarise how lung cancer is staged.

TNM Staging (Tumour, node, metastases)

Stage Description
T1 <3cm diameter without invasion
T2 • >3cm diameter
OR tumour of any size
• Invading pleura
• Atelectasis(collapsed) of less than entire young
• Proximal extent at least 2cm from carina (bifurcation of the
trachea)
T3 Tumour of any size:
• Invasion of chest wall
• Involvement of diaphragm, mediastinal pleura, pericardium

T4 Tumour of any size:

• Invasion of mediatinum, heart or great vessels, trachea,
oesophagus, vertebral body, bifurcation of trachea
• Presence of malignant pleural or pericardial effusion (fluid
around heart)
• Satellite tumour nodules within same lobe as primary tumour.

Stage Description
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N0 No regional node involvement

N1 Metastasis to ipsilateral (on the same side as tumour) hilar or
peribronchial nodes
N2 Metastasis to ipsilateral mediastinal or subcarinal nodes
N3 Metastasis to contralateral mediastinal or hilar nodes
OR ipsilateral or contralateral scalene or supraclavicular nodes

Stage Description
M0 Distant metastasis absent
M1 Distant metastasis present (includes tumour nodules in different lobe to
primary tumour

• Explain the modalities by which lung cancer can be diagnosed.

Clinical features:
• Haemoptysis
Unexplained or persistent:
• Cough
• Chest/shoulder pain
• Chest signs
• Dyspnoea
• Hoarseness
• Finger clubbing

Symptoms presented:
• None
• Local spread – Intrapulmonary, Invasion of adjacent tissue
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• Distant spread – small cell>adeno>large cell

• Paraneoplastic syndromes – Endocrine or non-endocrine

• Explain the consequences of the existence of a small proportion of drug

resistant cells within a tumour.
Tumour will appear in remission as non-resistant cells will die, but the resistant cells will
continue to proliferate – DISCEIVING.

• Describe the risk factors and basic pathology of mesothelioma.

Mesothelioma- tumour of the pleura
• <1% cancer deaths
• Increasing in incidence (expected to peak in 2010)
Risk factors: History of exposure to asbestos
• Long lag time
• 3:1 Male: female prevalence
• 50-70 years of age

• Give an approximate value for the survival rate of patients 5 years after the
initial diagnosis of lung cancer.
80% of people die within 1 year of diagnosis
5.5% survival rate for 5 years time

Respiratory system 10 – Allergy and Allergic

diseases
• To define "Allergy" and to distinguish it from related terms such as "Intolerance",
"Atopy" and "Hypersensitivity".

Allergy: exaggerated immunological response to a foreign substance (inhaled,

swallowed, injected or come into contact with eye or skin)

Atopy: individuals with a genetic predisposition to produce antibodies against allergen.

(e.g. allergic rhinitis, asthma, atopic eczema)
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Hypersensitivity: exaggerated response

Seasonal allergens: grass pollens, tree pollen, weed pollen, fungal spores

Causes of perenial rhinitis and asthma: cats, dogs, horses, house dust mite, alterneria,
cockroach.

• To understand the fundamental immunological mechanisms operative in common

allergic diseases

Atopic allergic disease

• Arise when
individuals produce
increased amounts of
IgE

Allergy is not a disease, it is

a mechanism that is
important in some diseases
all the time, and some part of
the time.

Summary of diagram:

Acute symptoms: sneezing,

itching, spasm of airway, rash, tissue swelling

• Allergen binds to IgE antibodies on surface of mast cell, cross-linking them

• This activates the mast cell, causing degranulation → histamine, leukotrienes are
released
• Acute symptoms are then shown
• Histamine causes fall in BP
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• Leukotrienes have more prolonged course of action, causing airway narrowing

and swelling

Chronic symptoms: blocked nose, on-going wheeziness

• Allergen binds to Th2 cell (CD4+)

• This causes the release of Th2 cytokines and Chemokines
• This leads to chronic symptoms

Non-atopic allergy

• Still involve abnormal immune responses to environmental agents

• May involve Th1

Atopic allergy Non-atopic allergy Intolerance

Allergic asthma Contact dermatitis Enzyme deficiency
Allergic rhinitis Extrinsic allergic alveolitis Migraine
Anaphylaxis Coeliac disease Irritable bowel syndrome
Skin allergies Bloating (due to wheat intolerance)

Summer hay fever (seasonal allergic conjunctivo-rhinitis)

• 12-15% children, 11-17% adults

• Caused by grass pollen, tree pollen, weed pollen
• Generally effects quality of life
• UK prevalence is highest in Europe

Asthma

• Symptoms: Cough, SOB, wheezing, chest tightness, secretions

• Intermittent, mild - allergy frequent
• Persistent manageable – allergy often important
• Chronic severe - infection important (not allergy)
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Atopic dermatitis (eczema)

• Acute – erythema, papules, vesicules

• Chronic – erythema, scaling, cell infiltration

The 3 above diseases have high proportion of overlap (i.e. someone with one is likely to
have at least 1 other during their lifetime)

Causes of anaphylaxis:

• Drugs
• Food (peanuts, shellfish)
• Insect sting
• Latex

Treatment: Epipen

• To appreciate the scope and burden of allergic diseases

• Significant impact on life of patient and family
• High cost to NHS
• Many consultations of primary care physicians in relation to allergy
• To understand possible reasons for the rising trends in allergic disease.
• Decrease in infectious disease mirrors rise in allergies and autoimmune diseases
• Hygiene hypothesis: Suggested that in Western countries, the developing
immune system has not been exposed to microbial antigens which stimulate Th1
cells.
• Th2 phenotype may be encourages by date of birth around the pollen season and
alterations in infant diet
• Alterations in target organ (e.g. asthmatic exposed to respiratory virus infections
and tobacco smoke, air pollutants)
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• Outline the principles of treatment of allergic diseases, including allergen

specific immunotherapy.

Diagnosis: History, physical examination, skin prick tests, blood RAST tests (for specific
IgE)
• Avoidance of allergen
• Anti-allergen medication
• Specific allergen immunotherapy (hyposensitisation/desensitization)

Example: Allergic Rhinitis

• Drugs to treat: antihistamine (relieves symptoms), topical corticosteroids (to
suppress inflammation)

Specific allergen immunotherapy

• administering increasing concentrations of allergenic extracts over long periods of
time
Mode of action [REVIEW- see further notes]
• IgG blocking antibodies that compete with IgE for allergen may prevent
aggregation of IgE complexes on mast cells through steric hinderance and
interfering with antigen trapping by IgE bound to antigen presenting cells
• Specific immunotherapy induces a shift in Th2 to a Th1 cytokine profile (Less
production of IL-4 and IL-5, more production of IFN-γ and IL-12). This can
inhibit late-phase allergic reaction, and over months/years can reduce early phase.
• Introduction of IL-10 secreting T regulatory cells is also important – induces non-
responsiveness to one epitope of a molecule which can transfer to whole
molecule, or other similar molecules etc.
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