Pathophysiology of Asthma Flashcards
What is Asthma?
A chronic inflammatory and obstructive disease of the airways
Describe the characteristics of Asthma
chronic condition
episodes of reversible airflow limitation
bronchial hyper-responsiveness
patient finds it difficult to breathe normally (dyspnoea)
Outline the process of how asthma causes airway dysfunction
Inflammation:
- Allergen inhalation (HDM, pollen) / exercise
- Immune system response
- Airway inflammation
Airway dysfunction:
- Impaired airway function
- Symptoms; wheeze, cough, dyspnoea
What are the 2 basic pathophysiological divisions of asthma?
- Inflammtory / immune response component
- Airway component
Describe the inflammatory / immune response component of asthma
Individual develops hypersensitivity to a specific stimulus
(e.g. an allergen ie. pollen / house dust mites)
causing an inflammatory response on subsequent exposures to that stimulus
Explain the airway component of asthma
Allergen-induced inflammation release mediators that affect cellular function, produces limitations in tissue function
ie. airflow resulting in the generation of symptoms:
- dyspnoea, excess mucus, cough
What is aetiology?
The factors which cause and lead to an individual developing the disease; are complex
What is asthma aetiology like?
complex and involves genetic and environmental factors
Describe the genetic aetiology of asthma
Genetics:
- parental asthma
- susceptibility genes
- (ADAM33, GSTP1-, FCεRI-ꞵ)
Which immunological development factors contribute to asthma?
- infant respiratory virus infection
- modern hygiene
- Cesarean delivery
What lifestyle factors can lead to asthma?
- urban dwelling
- pollution exposure
- poor diet
- obesity
What is the respiratory tree?
The network of airway structures gas must pass through in order to reach gas exchange surfaces
What is the role of airways?
Airways provide a passageway for air, enabling a sufficient quantity of air gets from atmosphere -> lungs and out again
What is the consequence of impaired airway function?
Limited ventilation of respiratory surfaces and lungs aren’t able to maintain homeostasis of blood gases (CO₂ and O₂) and acid-base balance
What is the relationship between airflow and resistance?
Airflow through airways is proportional to the level of airway resistance
How is airways resistance generated?
Air passing through the respiratory tree generates resistance when in contact with airway surfaces
What is resistance?
Force acting to reduce the flow of gas/fluid through a conduit (pipe)
What is the result of increased resistance on airflow?
More resistance = less airflow
Explain the effect of airway size on resistance using Poiseuille’s law
resistance ∝ 1/r⁴
as airway radius decreases, resistance increases, reducing airflow dramatically
How can we overcome the effect or radius on resistance?
Increasing pressure difference between the two ends of the conduit - this has physical limitations in the respiratory system
How does lumen size relate to airflow?
Airflow is proportional to airway lumen size
Any physiological changes that decrease airway lumen size will limit airflow
How does airway smooth muscle cell relaxation affect airflow?
Relaxed, larger smooth muscle cell
Increased luminal area
Decreased resistance
Increased Airflow
What is the effect on airflow, of airway smooth muscle cell contraction?
Contracted, smaller smooth muscle cells
Decreased luminal area
Increased resistance
Decreased flow
How does inflammation affect airflow?
Airway inflammation increases airway resistance and decreases airflow
What is airway smooth muscle (ASM)?
The layer of muscle within airway tissue which contracts and relaxes to modulate airway tone
What is the function of inflammatory mediators?
During an asthma attack, inflammatory mediators induce pathological changes to the airways
What pathological changes do inflammatory mediators induce?
- Contraction of ASMC
- Increased mucus secretions
- microvascular leak -> causes airway oedema & swelling
What is the result of the pathological changes caused by inflammatory mediators?
These changes combine to substantially:
- decrease airway lumen size
- increase airway resistance
- limit airflow
=> obstructs airways, generating symptoms
How does airflow type affect resistance ?
Turbulent airflow further increases resistance
What is the normal airflow type within airways?
Air typically flows through the airway in a laminar manner
- except at airway branching points where transitional or
mixed flow is produced
this reduces resistance as airflow isn’t impeded
What happens to airflow type when obstructions are present?
Airflow becomes turbulent increasing resistance as airflow is no longer unidrectional
Generates noise - wheezing observed in asthma patients
How do allergic asthma responses come about?
Allergic responses require prior exposure
What are the 2 stages involved in allergic asthma?
- Allergen sensitisation
- Allergic response
Outline the allergic asthma response
Sensitisation:
1. Allergen exposure (HDM, pollen)
2. Allergen encountered & processed by adaptive
immune system
3. Antibodies generated immune system ‘primed’
Allergic Response:
- Subsequent allergen exposure
- Allergen binds antibodies
- immune cell activation
- inflammatory response
- Symptoms generated
What is sensitisation?
When the immune system first encounters the allergen and develops an adaptive (Ab + lymphocyte mediated) response
What is an allergic response?
Where the allergen is subsequently re encountered, triggering adaptive immune response which was previously primed during sensitisation
This generates an inflammatory response within the airways
What occurs during sensitisation?
Involves the presentation of antigens to T cells and B cell antibody production
What are mast cells?
immune cells involved in responses to parasitic helminths infections, containing pro-inflammatory mediators such as:
- histamines
- leukotrienes
- prostaglandins
What are eosinophils?
Polymorphonuclear granulocytes involved in parasitic defence - heavily implicated in asthma
What is the role of Th2 cells in sensitisation?
Th2 will also secrete Th2 cytokines:
- IL-4: modulates immune response
- IL-5: promotes survival, proliferation + trafficking
- IL-13: modulate immune response
Describe the immune response produced by allergens in the airways
- Allergen inhaled -> enters airway tissue
- > this alone can stimulate innate immune system
- Encountered by APCs (dendritic cells & macrophages)
- patrol tissues searching for foreign particles to present
to adaptive immune system. - After allergen is engulfed and processed, antigen is
displayed externally - APC binds helper T cell to its TCR, presenting the
antigen to the T cell, activating it and enabling it to
mature → Th2 cell - Activated Th2 cell interacts with a B cell to initiate
class-switching, proliferation, & production of IgE
antibodies that bind the antigen present in the original
allergen. - IgE antibodies produced circulate and bind (via their
heavy chain/Fc region) to IgE (FcεRI) receptors on
granulocytes
What initiates an asthmatic response?
Triggered by allergen-induced degranulation and airway inflammation
What is the significance of histamine in allergic responses?
In most allergies, histamine released by mast cells plays a major role in the pathophysiological mechanism and are widely used to treat allergies in general
BUT ARE INEFFECTIVE FOR ASTHMA TREATMENT
Explain the immune response to asthma allergen exposure
- Upon subsequent re-exposures, antigen present in
allergen recognised by IgE molecules bound to mast
cells in airways. - Multiple IgE molecules are cross-linked by the allergen,
triggering degranulation, where granulocyte releases
inflammatory mediators. - These mediators* (e.g. prostaglandins, leukotrienes,
cytokines) bind to receptors present on multiple cell
types within the airway to induce pathological changes
What pathological changes are induced by the inflammatory mediators?
- ASMC contraction
- Microvascular leak (oedema)
- Mucus secretion via goblet cells
–> immediate effect is rapid bronchospasms and a sharp decrease in airflow due to the changes increasing resistance
What are the phases of the asthmatic response?
- early phase
- late phase
Due to dynamics of asthma, many patient experience asthma attacks in 2 phases
Describe the events occurring in the early phase of asthma
Early phase (0 - 1 hrs) acute bronchoconstriction brought about by initial wave of degranulation
Describe what happens in the late phase of the asthmatic response
Late phase (up to 12 hrs) Extended period in which symptoms initially improve before worsening at secondary inflammation and migration of Th2 and eosinophils to the airways
Which phase of asthma generates ‘night-time’ asthma?
The late phase of asthma
What are the characteristics of night time asthma?
- patient experiences allergens during the day
- uses inhaler to cope with acute phase of asthma attack
- medication wears off - breathing gradually worsens
What is the effect of hyperresponsiveness in the late phase of asthma?
Patients often experience airway hyperresponsiveness during the late phase - level of allergen exposure required to induce an attack is much lower
How does respiratory function change in obstructive respiratory failure?
FEV₁ decreases
FVC remains unchanged
FEV₁/FVC value decreases (<70%)
Why does airway remodelling occur?
Chronic, uncontrolled asthma can lead to negative long term changes in airway structure
Which phase of asthma generates ‘night-time’ asthma?
The late phase of asthma
What are the characteristics of night time asthma?
- patient experiences allergens during the day
- uses inhaler to cope with acute phase of asthma attack
- medication wears off - breathing gradually worsens
What is the effect of hyperresponsiveness in the late phase of asthma?
Patients often experience airway hyperresponsiveness during the late phase - level of allergen exposure required to induce an attack is much lower
How does respiratory function change in obstructive respiratory failure?
FEV₁ decreases
FVC remains unchanged
FEV₁/FVC value decreases (<70%)
Why does airway remodelling occur?
Chronic, uncontrolled asthma can lead to negative long term changes in airway structure
Explain the stages of airway remodelling
- Allergen exposure
- Inflammatory mediator response
- activates airway eosinophils + Th2
- bronchoconstriction, mucus hypersecretion, oedema
- Th2 + eosinophils cause tissue damage, remodelling
airways and inducing further inflammatory responses - chronic airway remodelling also causes
bronchoconstriction, mucus secretion and oedema
leading to symptoms
Why does airway remodelling occur?
If asthmatic inflammation is inadequately controlled over a long period, repeated waves of inflammation and tissue damage may eventually result in long term irreversible reductions in airway function => airway remodelling
What pathological changes are caused by airway remodelling?
- smooth muscle hypertrophy
- goblet cell hyperplasia; hypersecretion of viscous
mucus - immune cell infiltration
- disrupted epithelium (easy allergen access)
- Basement membrane thickening
- Possible fibrosis
What is the primary aim of airway remodelling treatment?
As the changes are irreversible, treatment aims to prevent airway function degeneration via adequate control of symptoms and inflammation
How is the binding of antibodies to IgE prevented?
anti-IgE mAb (omalizuma)
What is the effect of short acting beta-2 adrenoceptor agonists (e.g. salbutamol)?
Provide acute relief
Bronchodilation; relaxation of airway smooth muscle
Increase airway lumen size
Decreases airway resistance
Which treatments prevent ASMC contraction?
- beta-2 adrenoceptor agonist (salbutamol)
- muscarinic receptor antagonists (tiotropium)
How is mucus hypersecretion prevented?
muscarinic receptor agonists (tiotropium)
Corticosteroids
What treatments are used to treat airway oedema?
Corticosteroids
What are the 2 primary first line treatments for asthma patients?
- Short acting beta-2 adrenoceptor agonists (salbutamol)
- Inhaled corticosteroids (fluticasone)
What is the effect of short acting beta-2 adrenoceptor agonists (e.g. salbutamol)?
Provide acute relief
bronchodilation; relaxation of airway smooth muscle
Incease airway lumen size
Explain the effect of inhaled corticosteroids (e.g. fluticasone)?
Targets + reduces inflammation
Modulate cytokine expression
Inhibit proliferation, activation + chemotaxis of leukocytes
Reduces mucus secretion via goblet cells
What secondary treatments are available for asthma treatment?
- Leukotriene receptor antagonists
- Anti-IgE mAb (omalizumab)
- Anticytokine receptor antagonist (tiotropium)
Describe the effects of Muscarinic receptor antagonists like tiotropium
Block muscarinic receptors, inhibiting Ach effects
- Reduce mucus secretion
- relaxes Airway smooth muscle
What is the effect of Anti-IgE mAb (e.g. omalizumab)?
Binds the circulating IgE - neutralising it to reduce its role
Explain the effect of Leukotriene receptor Antagonists?
Inhibit effects of pro-inflammatory leukotriene mediators by blocking receptors
Why is personalised medicine so significant for asthma patients?
Asthma is complex and a heterogenous condition with multiple endotypes
personalised medicine is more effective for each patients needs
A 23 year old male asthmatic patient suffers acute breathing difficulties but takes their salbutamol inhaler and can soon breath much better.
What pathological change would best explain these changes?
a) Mucus hypersecretion
b) Airway smooth muscle contraction
c) Hypoxic vasoconstriction
d) Sympathetic nervous system activation
e) Airway remodelling
b) Airway smooth muscle contraction
