Patho-physiology of Asthma

Question 1

What is asthma? What are its two basic components?

Answer 1

• Asthma is a chronic, inflammatory and obstructive disease of the airways.
• It is typically categorised by episodes of reversible airflow limitation and bronchial hyperresponsiveness, where the patient experiences difficulty breathing (dyspnoea).
• The basic pathophysiology can be divided into two related components:
  
  • 1) An inflammatory/immune system response, in which the individual develops a hypersensitivity to a specific stimulus (typically an allergen, such as pollen or house dust mites), causing an inflammatory response (from the immune system) upon subsequent exposures to that stimulus.
  • 2) An airway dysfunction, where the allergen-induced inflammation releases mediators that affect cellular function, producing limitations in tissue function (ie. airflow), resulting in the generation of symptoms (dyspnoea, excess mucus and coughing).

Question 2

Asthma aetiology (causation of a disease) is complex and involves genetic and environmental factors. List a few of them.

Answer 2

MZ (Monozygotic) twins = Identical twins.

DZ (Dizygotic) twins = Non-identical twins.

Helminth meaning - It is a parasitic worm.

Question 3

Describe airway dysfunction in asthma.

Answer 3

• We know that airflow through the airways is inversely proportional to the level of airway resistance.
• Airflow is, therefore, proportional to the size of the lumen.
• Airway inflammation (swelling / oedema), excess mucus secretion, contraction of smooth muscle and irritation of sensory neurons (coughing) all increase airway resistance by decreasing luminal area and decrease airflow.
• Airway resistance is further increased by turbulent airflow.

Question 4

Allergic responses require prior-exposure and sensitisation. Describe how this occurs.

Answer 4

• ALLERGEN SENSITISATION: (first time an individual encounters the allergen)
  
  • The body is exposed to the allergen (e.g. HDM, pollen, etc.).
  • The allergen is encountered and processed by the adaptive immune system (T cells and B cells).
  • Antibodies are generated, and thus the immune system is ‘primed’.
• ALLERGIC RESPONSE: (the 2-3 exposure to the allergen after sensitisation)
  
  • There is a subsequent (same) allergen exposure.
  • The allergen binds to the antibodies, causing an inflammatory response and immune cell activation.
  • This causes the subsequent symptoms.

Question 5

Describe the mechanism of how sensitisation to allergens occurs in the immune system.

Answer 5

1. The allergen is inhaled and enters the airway tissue, encountering an antigen-presenting cell (APC).
2. The APC engulfs and processes the allergen.
3. It then presents the allergen to a naïve helper T-cell (CD4+ T-cell).
4. The mature T_h2-cell releases IL-5, which activates eosinophils (eosinophil proliferation) which migrate to different airway structures.
5. The mature Th2-cell also interacts with a B-cell displaying antigen, causing the B-cell to proliferate and produce IgE antibodies.
6. The IgE antibodies bind to FcεRI-β (IgE) receptors on mast cells.

Question 6

Explain how the asthmatic allergic response is mediated after the second exposure to allergens.

Answer 6

1. The allergens are inhaled for the second time and they bind to the IgE antibodies on the mast cells, inducing their degranulation (where the granulocyte releases its contents of inflammatory mediators). [Inflammatory mediators include prostaglandins, leukotrienes, chemokines, etc.]
2. These mediators then bind to receptors present on multiple cell types within the airways to induce pathological changes, including contraction of airway smooth muscle, microvascular leakage (oedema) and activation of goblet cells (mucus secretion).
3. The immediate effect of mediator release is rapid bronchospasm and a sharp decrease in airflow (due to the increase in airway resistance brought about by these mediators). [NOTE: In asthma, histamine plays a minor role].
4. However, the release of these mediators also induces secondary pro-inflammatory changes, as they activate other immune cells (Th2 cells and eosinophils), triggering a wave of mediators to be released.
5. The eosinophils migrate to the airways and release inflammatory mediators such as reactive oxygen species, leukotrienes and toxic enzymes.
6. The Th2 cells release inflammatory mediators such as IL-4, IL-5 and IL-13.
7. The net effect of this is a prolonged decrease in airway function until the inflammation is resolved.

Question 7

Explain the early and late phases that may happen in the asthmatic response to allergen.

Answer 7

• Not always does an asthmatic individual get a late response but often after the first asthma attack they are hypersensitive.
• This means that the individual is much more likely to experience a further asthma attack because the airway is already in an inflammed state.

Question 8

What happens in chronic, uncontrolled asthma that causes permanent and non-reversible change in the airway structure?

Answer 8

• If asthmatic inflammation is inadequately controlled over a prolonged period, the repeated waves of inflammation and tissue damage may eventually result in long term irreversible reductions in airway function known as airway remodelling.
• These pathological changes include smooth muscle hypertrophy, increased secretion of highly-viscous mucus and goblet cell hyperplasia, immune cell infiltration, disrupted epithelium (enabling greater infiltration of allergens), basement membrane thickening, and possible fibrosis.
• As these changes are currently irreversible, one of the primary aims of treatment is to prevent degeneration of airway function via adequate control of symptoms and inflammation.

Hypertrophy meaning - It is the enlargement or overgrowth of an organ or part due to an increase in size of its constituent cells.

Hyperplasia meaning - It is an increase in the amount of organic tissue that results from cell proliferation. It may lead to the gross enlargement of an organ.

Infilteration meaning - The diffusion or accumulation in a tissue or cells of substances not normal to it or in amounts of the normal.

Question 9

List some pharmacological treatments for asthma.

Answer 9

The most effective are β-2 adrenoreceptor agonists and corticosteroids as they work on the patients symptoms that are generally shared between all asthma patients.

Question 10

Why are the symptoms shown between asthma patients different?

Answer 10

• Asthma is a complex & heterogeneous condition with multiple endotypes (sub-types).
• This makes it difficult to treat as the causes of the disease for different people can be different. So the same drug may not necessarily work on everybody.