Patho-Physiology Of Asthma

Question 1

What is asthma?

Answer 1

Asthma is a chronic, inflammatory and obstructive disease of the airways. 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 upon subsequent exposures to that stimulus.
2) An airway component, 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

GENETICS:
- parental asthma susceptibility genes (such as ADAM33, GSTP1-, FcεRI-β)

IMMUNOLOGICAL DEVELOPMENT:

• infant respiratory viral infection
• caesarean delivery

LIFESTYLE:

• urban dwelling
• pollution exposure
• poor diet
• obesity

Question 3

Describe airway dysfunction in asthma.

Answer 3

We know that airflow through the airways is proportional to the level of airway resistance. Airflow is, therefore, proportional to the size of the lumen.
Airway inflammation, excess mucus secretion, contraction of smooth muscle and irritation of sensory neurons (coughing) all increase airway resistance 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:
The body is exposed to the allergen (e.g. HDM, pollen, etc.).
The allergen is encountered and processed by the adaptive immune system.
Antibodies are generated, and thus the immune system is ‘primed’.

ALLERGIC RESPONSE:
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

Sensitisation involves the presentation of antigens to T-cells and B-cell antibody production.
Describe the mechanisms underlying this.

Answer 5

The allergen is inhaled and enters the airway tissue, encountering an antigen-presenting cell.
The APC engulfs and processes the allergen. It then presents the allergen to a naïve helper T-cell.
The Th2-cell releases IL-5, which activates eosinophils. The Th2-cell also interacts with a B-cell displaying antigen, causing the B-cell to proliferate and produce IgE antibodies.
The IgE antibodies bind to FcεRI-β (IgE) receptors on mast cells.

Question 6

The asthmatic response is triggered by allergen-induced degranulation and airway inflammation.
How does this come about?

Answer 6

Multiple IgE molecules are cross-linked by the allergen, triggering degranulation, where the granulocyte releases its contents of inflammatory mediators. 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).

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].

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 (Th2 cells release IL-4, IL-5 and IL-13, and eosinophils release reactive oxygen species, leukotrienes and toxic enzymes).
The net effect of this is a prolonged decrease in airway function until the inflammation is resolved.

Question 7

Chronic uncontrolled asthma can lead to negative long-term changes in airway structure.
List some of the possible changes.

Answer 7

The pathological changes include:

• smooth muscle hypertrophy
• increased secretion of highly-viscous mucus (goblet cell hyperplasia)
• immune cell infiltration
• disrupted epithelium (easier access for allergens)
• basement membrane thickening
• possible fibrosis

Question 8

List some pharmacological treatments for asthma.

Answer 8

• Anti-IgE mAb (monoclonal antibody) (such as omalizumab)
• Corticosteroids (fluticasone)
• Leukotriene receptor antagonists (montelukast)
• IL-4, IL-5, IL-13 mAb
• β-2 adrenoreceptor agonists (salbutamol)
• muscarinic receptor antagonists (tiotropium)