Pathophysiology of asthma Flashcards

1
Q

What is asthma?

A

Asthma is a chronic inflammatory condition which involves airflow limitation and bronchial hyperresponsiveness, where the patient has trouble breathing.

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2
Q

The pathophysiology of asthma can be divided into 2 aspects, what are these aspects?

A

1) An inflammatory/immune system component, in which the individual develops hypersensitivity to a specific stimulus (typically an allergen such as pollen or house dust mites), causing an inflammatory response upon subsequent exposures to that stimulus.
2) An airway component, where the allergen-induced inflammation release mediators that affect cellular function, produce limitations in tissue function (i.e. airflow), resulting in the generation of symptoms (dyspnoea, excess mucus, and cough).

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3
Q

In asthma what is the velocity and volume of airflow inversely proportional to?

A

The level of airway resistance present, resistance being primarily determined by the cross-sectional area of the airway lumen and the turbulence of airflow.

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4
Q

What does Ohms law state?

A

Airflow (V) is proportional to 1/Resistance.

So more resistance is equal to less airflow

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5
Q

What is the Hagen Poiseuille equation

A

Resistance (R) is proportional to 1/Radius^4

As an airways radius decreases, the resistance increases and airflow decreases dramatically

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6
Q

Describe what pathological changes occur in an asthmatic airway caused by inflammation

A
  1. Contraction of smooth muscle
  2. Excess mucus secretion
  3. Oedema/ swelling
  4. Irritation of sensory neurones (cough)

Luminal area decreases
airway resistance increases
reduced airflow

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7
Q

Describe the two stages of allergic asthma

A
  1. Sensitisation - where the immune system first encounters the allergen and develops an adaptive (antibody- and lymphocyte-mediated) immune response.
  2. The allergic response – where the allergen is subsequently re-encountered, triggering the adaptive response previous primed during sensitisation. This generates an inflammatory response within the airways, producing symptoms.
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8
Q

Describe the process of Sensitisation in detail (7 marks)

A
  • The allergen is inhaled into the airway tissue
  • This causes the airway to release pro-inflammatory signals. The allergen is then encountered by the antigen presenting cells e.g dendritic or macrophages which search for foreign particles
  • A fragment of allergen Is then displayed externally. So when an APC encounters a native T-helper cell with the appropriate T-cell receptor, the antigen will be presented to the T-cell, activating it and enabling it to mature into a Th2 cell, depending on the cytokine environment
  • The activated Th2 cell then interacts with a B cell to initiate class-switching (the class of Ig antibody the B cell produces), proliferation, and production of IgE antibodies that bind the antigen present in the original allergen.
  • The IgE antibodies produced then circulate and bind (via their heavy chain/Fc region) to IgE (FcεRI) receptors on granulocytes such as mast cells.
  • When IgE is bound to its receptor in this way, the light chain/Fab region is still displayed, enabling antigen binding
  • During sensitisation, Th2 cells will also secrete ‘Th2 cytokines’ such as IL-4, IL-5 and IL-13, which act to modulate the immune system. IL-5 in particular promotes survival, proliferation and trafficking (e.g. to the airways) of eosinophils
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9
Q

Describe the process of the immune response to an allergen (6 marks)

A
  • Upon subsequent re-exposures, the antigens within the allergen are recognised by IgE molecules bound to mast cells within the airways. Multiple IgE molecules are cross-linked by the allergen, triggering degranulation, where the granulocyte releases its contents of inflammatory mediators.
  • These mediators (e.g. prostaglandins, leukotrienes, cytokines) then bind to receptors present on multiple cell types within the airway that induce pathological changes, such as contraction of airway smooth muscle cells, microvascular leak (oedema), stimulation of goblet cells (mucus secretion), and activation of eosinophils, another granulocyte within the airways, triggering further release of inflammatory mediators.
  • The immediate effect of this process is rapid bronchospasm and a sharp decrease in airflow (due to the increase in airway resistance brought about by these changes).
  • It should be noted at this point that in contrast to many allergies, histamine release from mast cells appears to play a very limited role in the pathophysiology of asthma. Whilst drugs which block histamine receptors (anti-histamines) are one of the primary treatments for allergies in general, they are ineffective at treating asthma.
  • At the same time as activating mast cell degranulation, the presence of allergen within the airways also induces further activation of Th2 cells, which often induces secondary pro-inflammatory changes several hours later, as Th2 cytokine release induces eosinophils trafficking to the airways, where they become activated and release further pro-inflammatory mediators.
  • Th2 cells release IL-4, IL-5 and IL¬¬ 13, eosinophils release reactive oxygen species, leukotrienes and proteolytic enzymes. The net effects of this can be a second decrease in airway function and period of airway hyper-responsiveness (a period where the threshold of allergen exposure required to elicit further asthma attacks is greatly reduced).
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10
Q

What is airway remodelling and when can it occur?

A

Airway remodeling = the long term, negative structural changes (fibrosis, goblet cell hyperplasia, epithelium disruption) that can occur in patients with severe, poorly-controlled asthma, which results from repeated inflammation-induced tissue injury.

Airway remodeling is associated with a progressive, irreversible decline in airway and respiratory function (↑obstruction, ↓FEV1, respiratory failure)

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11
Q

Which patients does airway remodelling particular occur in?

A

Patients with severe, ‘poorly controlled’ asthma, where a patient’s symptoms and inflammation are not adequately controlled by drugs such as corticosteroids.

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