Pathophysiology of asthma

Question 1

What is asthma?

Answer 1

A chronic, inflammatory and obstructive disease of the airways
Asthma is a complex and heterogenous condition with multiple endotypes

Question 2

Describe how inflammation can lead to airway dysfunction

Answer 2

1. Allergen inhalation (HDM, pollen) OR exercise triggers the immune response
   
   2. Mast cells, eosinophils, Th2 cells all respond to the trigger, causing airway inflammation
   3. This inflammation impairs airway function
      Some symptoms are:
      • Wheeze
      • Cough
      Dyspnoea

Question 3

Describe how genetics, immunological development and lifestyle can make an individual more likely to develop asthma

Answer 3

GENETICS:
• Parental asthma
• Susceptibility genes: ADAM33, GSTP1-, FcERI-B

IMMUNOLOGICAL DEVELOPMENT:
• Infant respiratory viral infection
• Modern hygiene
• Caesarean delivery

LIFESTYLE:
	• Urban dwelling
	• Pollution exposure 
	• Poor diet 
Obesity

Question 4

Describe how genetics, immunological development and lifestyle can make an individual less likely to develop asthma

Answer 4

GENETICS:
• No parental asthma
• Protective genes: GSPT1+

IMMUNOLOGICAL DEVELOPMENT:
	• Helminth exposure 
	• Healthy microbiota 
	• Vaginal delivery 
	• Older siblings 

LIFESTYLE:
• Rural dwelling
• Lower pollution environment
Healthy diet

Question 5

What does an impaired airway function lead to?

Answer 5

Impaired airway = insufficient ventilation
This leads to:
- Less blood gas homeostasis
- Less acid-base balance

Question 6

Describe in detail how airway resistance can be increased

Answer 6

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 7

Describe the difference between a healthy airway and an asthmatic airway and state the overall effect of these changes

Answer 7

• Smaller lumen
  
  • Contraction of smooth muscle is greater
  • Excess mucus secretion
  • Oedema/swelling
  • Irritation of sensory neurons resulting in a cough
    The overall effect is a smaller luminal area = increased airway resistance = decreased airflow

Question 8

Describe what type of airflow increases airway resistance in an asthmatic

Answer 8

Airway resistance is further increased by turbulent airflow

Question 9

Allergic responses require prior-exposure and sensitisation;
Describe how this occurs in terms of the trigger and response

Answer 9

1. Allergen exposure (HDM, pollen)
   
   2. Allergen encountered and processed by adaptive immune system
   3. Antibodies are generated and immune system is ‘primed’
   4. Subsequent allergen exposure occurs
   5. Allergen then binds to antibodies
      Immune cell activation
      Inflammatory response

Question 10

Sensitisation involves presentation of antigens to T cells, and B cell-Ab production. Describe this process in detail

Answer 10

1. Allergen inhaled enters the airway tissue, encountering and antigen presenting cell (APC: dendritic cells)
   
   2. APC then engulfs and processes the allergen and presents the antigen to the naïve helper T cell (CD4+)
   3. Mature Th2 cell releases IL-5 = activating eosinophils
      Mature Th2 cell interacts with B cell displaying antigen = B cell proliferates = produces IgE antibodies
2. IgE antibodies bind to IgE receptors (FcεRI-β) on mast cells

Question 11

The asthmatic response is triggered by allergen induced degranulation and airway inflammation. Describe this process in detail.

Answer 11

1. Allergen inhaled enters airway tissue
   
   2. Allergen binds and cross-links IgE antibodies on mast cells, inducing degranulation
   3. Mast cell degranulation releases inflammatory mediators (PGs, LTs and chemokines)
      Airway inflammation reduces airflow and generates symptoms:
      • Contraction of vascular smooth muscle
      • Excess mucus secretion
      • Oedema/swelling
   4. Inflammatory mediators activate Th2 cells and eosinophils
      Th2 cells release IL-4, IL-5, IL-13
   5. Eosinophils recruited to the airways where they release further mediators and reactive oxygen species (ROS); this again generates symptoms:
      • Contraction of vascular smooth muscle
      • Excess mucus secretion
      • Oedema/swelling

Question 12

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

Answer 12

Acute asthma = tissue damage 
Chronic asthma:
	• Smooth muscle hypertrophy 
	• Mucus hypersecretion 
	• Bronchoconstriction 
	• Airway oedema
	• Immune cell infiltration 
	• Excess mucus and goblet cells 
	• Basement membrane thickening 
	• Extracellular matrix deposition and fibrosis 
Epithelium disruption

Question 13

List some pharmacological treatments for asthma

Answer 13

• omalizumab: monoclonal antibody Anti-IgE mAb
• Fluticasone: corticosteroid
Treats airway inflammation
• Montelukast: leukotriene receptor antagonist
Treats airway inflammation
• IL-4, IL-5, IL-13 mAb: monoclonal antibody
Treats airway inflammation
• Salbutamol: beta-2 adrenergic receptor agonist
Airway smooth muscle contraction
• Tiotropium: muscarinic receptor antagonist
Airway smooth muscle contraction
Treats mucus secretion
• Corticosteroids
Treats mucus secretion
Oedema