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Respiratory System > Pathophysiology of Asthma > Flashcards

Pathophysiology of Asthma Flashcards

1
Q

What is Asthma?

A

A chronic inflammatory and obstructive disease of the airways

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2
Q

Describe the characteristics of Asthma

A

chronic condition
episodes of reversible airflow limitation
bronchial hyper-responsiveness
patient finds it difficult to breathe normally (dyspnoea)

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3
Q

Outline the process of how asthma causes airway dysfunction

A

Inflammation:

  1. Allergen inhalation (HDM, pollen) / exercise
  2. Immune system response
  3. Airway inflammation

Airway dysfunction:

  1. Impaired airway function
  2. Symptoms; wheeze, cough, dyspnoea
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4
Q

What are the 2 basic pathophysiological divisions of asthma?

A
  • Inflammtory / immune response component

- Airway component

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5
Q

Describe the inflammatory / immune response component of asthma

A

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

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6
Q

Explain the airway component of asthma

A

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

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7
Q

What is aetiology?

A

The factors which cause and lead to an individual developing the disease; are complex

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8
Q

What is asthma aetiology like?

A

complex and involves genetic and environmental factors

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9
Q

Describe the genetic aetiology of asthma

A

Genetics:

  • parental asthma
  • susceptibility genes
  • (ADAM33, GSTP1-, FCεRI-ꞵ)
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10
Q

Which immunological development factors contribute to asthma?

A
  • infant respiratory virus infection
  • modern hygiene
  • Cesarean delivery
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11
Q

What lifestyle factors can lead to asthma?

A
  • urban dwelling
  • pollution exposure
  • poor diet
  • obesity
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12
Q

What is the respiratory tree?

A

The network of airway structures gas must pass through in order to reach gas exchange surfaces

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13
Q

What is the role of airways?

A

Airways provide a passageway for air, enabling a sufficient quantity of air gets from atmosphere -> lungs and out again

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14
Q

What is the consequence of impaired airway function?

A

Limited ventilation of respiratory surfaces and lungs aren’t able to maintain homeostasis of blood gases (CO₂ and O₂) and acid-base balance

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15
Q

What is the relationship between airflow and resistance?

A

Airflow through airways is proportional to the level of airway resistance

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16
Q

How is airways resistance generated?

A

Air passing through the respiratory tree generates resistance when in contact with airway surfaces

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17
Q

What is resistance?

A

Force acting to reduce the flow of gas/fluid through a conduit (pipe)

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18
Q

What is the result of increased resistance on airflow?

A

More resistance = less airflow

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19
Q

Explain the effect of airway size on resistance using Poiseuille’s law

A

resistance ∝ 1/r⁴

as airway radius decreases, resistance increases, reducing airflow dramatically

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20
Q

How can we overcome the effect or radius on resistance?

A

Increasing pressure difference between the two ends of the conduit - this has physical limitations in the respiratory system

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21
Q

How does lumen size relate to airflow?

A

Airflow is proportional to airway lumen size

Any physiological changes that decrease airway lumen size will limit airflow

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22
Q

How does airway smooth muscle cell relaxation affect airflow?

A

Relaxed, larger smooth muscle cell
Increased luminal area
Decreased resistance
Increased Airflow

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23
Q

What is the effect on airflow, of airway smooth muscle cell contraction?

A

Contracted, smaller smooth muscle cells
Decreased luminal area
Increased resistance
Decreased flow

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24
Q

How does inflammation affect airflow?

A

Airway inflammation increases airway resistance and decreases airflow

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25
Q

What is airway smooth muscle (ASM)?

A

The layer of muscle within airway tissue which contracts and relaxes to modulate airway tone

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26
Q

What is the function of inflammatory mediators?

A

During an asthma attack, inflammatory mediators induce pathological changes to the airways

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27
Q

What pathological changes do inflammatory mediators induce?

A
  • Contraction of ASMC
  • Increased mucus secretions
  • microvascular leak -> causes airway oedema & swelling
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28
Q

What is the result of the pathological changes caused by inflammatory mediators?

A

These changes combine to substantially:

  • decrease airway lumen size
  • increase airway resistance
  • limit airflow

=> obstructs airways, generating symptoms

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29
Q

How does airflow type affect resistance ?

A

Turbulent airflow further increases resistance

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30
Q

What is the normal airflow type within airways?

A

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

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31
Q

What happens to airflow type when obstructions are present?

A

Airflow becomes turbulent increasing resistance as airflow is no longer unidrectional
Generates noise - wheezing observed in asthma patients

32
Q

How do allergic asthma responses come about?

A

Allergic responses require prior exposure

33
Q

What are the 2 stages involved in allergic asthma?

A
  • Allergen sensitisation

- Allergic response

34
Q

Outline the allergic asthma response

A

Sensitisation:
1. Allergen exposure (HDM, pollen)
2. Allergen encountered & processed by adaptive
immune system
3. Antibodies generated immune system ‘primed’

Allergic Response:

  1. Subsequent allergen exposure
  2. Allergen binds antibodies
    • immune cell activation
    • inflammatory response
  3. Symptoms generated
35
Q

What is sensitisation?

A

When the immune system first encounters the allergen and develops an adaptive (Ab + lymphocyte mediated) response

36
Q

What is an allergic response?

A

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

37
Q

What occurs during sensitisation?

A

Involves the presentation of antigens to T cells and B cell antibody production

38
Q

What are mast cells?

A

immune cells involved in responses to parasitic helminths infections, containing pro-inflammatory mediators such as:

  • histamines
  • leukotrienes
  • prostaglandins
39
Q

What are eosinophils?

A

Polymorphonuclear granulocytes involved in parasitic defence - heavily implicated in asthma

40
Q

What is the role of Th2 cells in sensitisation?

A

Th2 will also secrete Th2 cytokines:

  • IL-4: modulates immune response
  • IL-5: promotes survival, proliferation + trafficking
  • IL-13: modulate immune response
41
Q

Describe the immune response produced by allergens in the airways

A
  1. Allergen inhaled -> enters airway tissue
    • > this alone can stimulate innate immune system
  2. Encountered by APCs (dendritic cells & macrophages)
    - patrol tissues searching for foreign particles to present
    to adaptive immune system.
  3. After allergen is engulfed and processed, antigen is
    displayed externally
  4. APC binds helper T cell to its TCR, presenting the
    antigen to the T cell, activating it and enabling it to
    mature → Th2 cell
  5. 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.
  6. IgE antibodies produced circulate and bind (via their
    heavy chain/Fc region) to IgE (FcεRI) receptors on
    granulocytes
42
Q

What initiates an asthmatic response?

A

Triggered by allergen-induced degranulation and airway inflammation

43
Q

What is the significance of histamine in allergic responses?

A

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

44
Q

Explain the immune response to asthma allergen exposure

A
  1. Upon subsequent re-exposures, antigen present in
    allergen recognised by IgE molecules bound to mast
    cells in airways.
  2. Multiple IgE molecules are cross-linked by the allergen,
    triggering degranulation, where granulocyte releases
    inflammatory mediators.
  3. These mediators* (e.g. prostaglandins, leukotrienes,
    cytokines) bind to receptors present on multiple cell
    types within the airway to induce pathological changes
45
Q

What pathological changes are induced by the inflammatory mediators?

A
  • 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

46
Q

What are the phases of the asthmatic response?

A
  • early phase
  • late phase

Due to dynamics of asthma, many patient experience asthma attacks in 2 phases

47
Q

Describe the events occurring in the early phase of asthma

A 
Early phase (0 - 1 hrs)
acute bronchoconstriction brought about by initial wave of degranulation
48
Q

Describe what happens in the late phase of the asthmatic response

A 
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
49
Q

Which phase of asthma generates ‘night-time’ asthma?

A

The late phase of asthma

50
Q

What are the characteristics of night time asthma?

A
  • patient experiences allergens during the day
  • uses inhaler to cope with acute phase of asthma attack
  • medication wears off - breathing gradually worsens
51
Q

What is the effect of hyperresponsiveness in the late phase of asthma?

A

Patients often experience airway hyperresponsiveness during the late phase - level of allergen exposure required to induce an attack is much lower

52
Q

How does respiratory function change in obstructive respiratory failure?

A

FEV₁ decreases
FVC remains unchanged
FEV₁/FVC value decreases (<70%)

53
Q

Why does airway remodelling occur?

A

Chronic, uncontrolled asthma can lead to negative long term changes in airway structure

54
Q

Which phase of asthma generates ‘night-time’ asthma?

A

The late phase of asthma

55
Q

What are the characteristics of night time asthma?

A
  • patient experiences allergens during the day
  • uses inhaler to cope with acute phase of asthma attack
  • medication wears off - breathing gradually worsens
56
Q

What is the effect of hyperresponsiveness in the late phase of asthma?

A

Patients often experience airway hyperresponsiveness during the late phase - level of allergen exposure required to induce an attack is much lower

57
Q

How does respiratory function change in obstructive respiratory failure?

A

FEV₁ decreases
FVC remains unchanged
FEV₁/FVC value decreases (<70%)

58
Q

Why does airway remodelling occur?

A

Chronic, uncontrolled asthma can lead to negative long term changes in airway structure

59
Q

Explain the stages of airway remodelling

A
  1. Allergen exposure
  2. Inflammatory mediator response
    • activates airway eosinophils + Th2
    • bronchoconstriction, mucus hypersecretion, oedema
  3. Th2 + eosinophils cause tissue damage, remodelling
    airways and inducing further inflammatory responses
  4. chronic airway remodelling also causes
    bronchoconstriction, mucus secretion and oedema
    leading to symptoms
60
Q

Why does airway remodelling occur?

A

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

61
Q

What pathological changes are caused by airway remodelling?

A
  • smooth muscle hypertrophy
  • goblet cell hyperplasia; hypersecretion of viscous
    mucus
  • immune cell infiltration
  • disrupted epithelium (easy allergen access)
  • Basement membrane thickening
  • Possible fibrosis
62
Q

What is the primary aim of airway remodelling treatment?

A

As the changes are irreversible, treatment aims to prevent airway function degeneration via adequate control of symptoms and inflammation

63
Q

How is the binding of antibodies to IgE prevented?

A

anti-IgE mAb (omalizuma)

64
Q

What is the effect of short acting beta-2 adrenoceptor agonists (e.g. salbutamol)?

A

Provide acute relief
Bronchodilation; relaxation of airway smooth muscle
Increase airway lumen size
Decreases airway resistance

65
Q

Which treatments prevent ASMC contraction?

A
  • beta-2 adrenoceptor agonist (salbutamol)

- muscarinic receptor antagonists (tiotropium)

66
Q

How is mucus hypersecretion prevented?

A

muscarinic receptor agonists (tiotropium)

Corticosteroids

67
Q

What treatments are used to treat airway oedema?

A

Corticosteroids

68
Q

What are the 2 primary first line treatments for asthma patients?

A
  • Short acting beta-2 adrenoceptor agonists (salbutamol)

- Inhaled corticosteroids (fluticasone)

69
Q

What is the effect of short acting beta-2 adrenoceptor agonists (e.g. salbutamol)?

A

Provide acute relief
bronchodilation; relaxation of airway smooth muscle
Incease airway lumen size

70
Q

Explain the effect of inhaled corticosteroids (e.g. fluticasone)?

A

Targets + reduces inflammation
Modulate cytokine expression
Inhibit proliferation, activation + chemotaxis of leukocytes
Reduces mucus secretion via goblet cells

71
Q

What secondary treatments are available for asthma treatment?

A
  • Leukotriene receptor antagonists
  • Anti-IgE mAb (omalizumab)
  • Anticytokine receptor antagonist (tiotropium)
72
Q

Describe the effects of Muscarinic receptor antagonists like tiotropium

A

Block muscarinic receptors, inhibiting Ach effects

  • Reduce mucus secretion
  • relaxes Airway smooth muscle
73
Q

What is the effect of Anti-IgE mAb (e.g. omalizumab)?

A

Binds the circulating IgE - neutralising it to reduce its role

74
Q

Explain the effect of Leukotriene receptor Antagonists?

A

Inhibit effects of pro-inflammatory leukotriene mediators by blocking receptors

75
Q

Why is personalised medicine so significant for asthma patients?

A

Asthma is complex and a heterogenous condition with multiple endotypes
personalised medicine is more effective for each patients needs

76
Q

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

A

b) Airway smooth muscle contraction

Respiratory System (10 decks)

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