S2: Pathophysiology of Asthma

Question 1

What is asthma?

Answer 1

Chronic, inflammatory & obstructive disease of the airways

Question 2

What are the two components of the pathophysiology of asthma?

Answer 2

1.INFLAMMATION/IMMUNE SYSTEM RESPONSE
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. AIRWAY DYSFUNCTION
   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)

Question 3

List factors than make an individual more likely to develop asthma

Answer 3

Genetics ~

• Parental asthma
• Susceptibility genes

Immunological development ~

• Infant respiratory virus infection
• Modern hygiene
• Caserean delivery

Lifestyle~

• Urban dwelling
• Pollution exposure
• Poor diet
• Obesity

Question 4

List factors than make an individual less likely to develop asthma

Answer 4

Genetics~

• No parental asthma
• Protective genes

Immunological development~

• Helminth exposure
• Healthy microbiota
• Vaginal delivery
• Older siblings

Lifestyle~

• Rural dwelling
• Lower pollution enviroment
• Healthy diet

Question 5

How does impaired airway function affect ventilation?

Answer 5

· Impaired airway function = insufficient ventilation which leads to decreased blood gas homeostasis and acid-base balance

Question 6

What is Ohms law?

Answer 6

Airflow through airways is proportional to level of airway resistance

Airflow(V) = Change in pressure (P) / Resistance (R)

Airflow (V) = 1/Resistance (R)

• More resistance = less airflow
• Unless pressure gradient is increased to compensate

Question 7

What is Hagen-Poiseulle equation?

Answer 7

Resistance (R) = 1/radius4
R= 8nl/Pi r4

• As an airway radius decreases, the resistance increases (and the airflow decreases) drastically
• Small changes in radius change to resistance
• Bigger airways causes less resistance than smaller airways

Question 8

What happens to airflow when size of lumen decreases?

Answer 8

Airflow is therefore proportional to the size (cross sectional area and radius) of the airway lumen.

Any physiological changes which decrease airway lumen size with limit airflow.

Decrease in luminal area = increases resistance and decreases flow

Question 9

Describe airway inflammation

Answer 9

Airway inflammation increases airway resistance and decreases airflow

Asthmatic airway:

• Contraction of smooth muscle (decreases radius increases resistance)
• Excess mucus secretion
• Oedema/swelling

Question 10

What changes happen to the airway during an asthma attack?

Answer 10

• Inflammatory mediators induce pathological changes to the airway including contraction of airway smooth muscle
• Increased mucus secretion and microvascular leak, which acts to cause airway oedema and swelling

These changes combine to substantially decrease the size of the airway lumen, increase airway resistance, and limit airflow (obstructing the airways and hence generating symptoms).

Question 11

What is turbulent airflow?

Answer 11

Airway resistance is increased produces turbulent airflow

• Generates a wheezing sound
• Presence of airway obstructions

Question 12

What are the two stages of allergic asthma?

Answer 12

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 to trigger the adaptive response previous primed during sensitisation. This generates an inflammatory response within the airway, producing symptoms

Question 13

Describe sensitation in allergic asthma

Answer 13

• Allergen is inhaled and enters airway tissue triggers the epithelium to release proinflammatory signals. It is encountered by antigen presenting cells (APCs) which patrol tissues searching for foreign particles to present to the adaptive immune system.
• After engulfing and processing the allergen, a antigen fragment is displayed externally so that when the APC encounters a naiive helper T cell with T cell . The antigen will be presented to the T cell activating it and enabling it to mature into a Th2 (CD4+) cell depending on the cytokine enviroment
• The activated Th2 cell then interacts with a B cell to initiate class switching, proliferation and production of IgE antibodies that bind the antigen present in the original allergen
• IgE antibodies produced then circulate and bind (via heavy chain/Fc region) to IgE receptors on granulocytes such as mast cells.
• When IgE is bound to its receptor in this way, the Fab region/light chain is 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 (another polymorphonuclear granulocyte with roles in parasite defence that is heavily implicated in asthma).

Question 14

Name some antigen presenting cell

Answer 14

Dendritic cells

Macrophages

Question 15

What are mast cells?

Answer 15

Immune cells involved in responses to parasitic helminths infections, which contain granules containing pro-inflammatory mediators such as histamine, leukotrienes and prostaglandins

Question 16

What cytokines do Th2 cells secrete during senitisation?

Answer 16

IL-4, IL-5 and IL-13

Question 17

What does IL-5 do?

Answer 17

IL-5 in particular promotes survival, proliferation and trafficking (e.g. to the airways) of eosinophils (another polymorphonuclear granulocyte with roles in parasite defence that is heavily implicated in asthma).

Question 18

Describe the allergic asthma in allergic asthma

Answer 18

• Upon subsequent re-exposures, the antigen present in the allergen is 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 to induce pathological changes including contraction of airway of SM cells, microvascular leakage (oedema), activation of goblet cells (mucus secretion). This causes rapid bronchospasm and sharp decrease in airflow (inc. airway resistance).
• Release of mediators also induces secondary pro-inflammatory changes as they activate other immune cells (Th2 and eosinophils) triggering more inflammation (mediators).
• IL-4, IL-5 and IL-13 eosinophils release reactive oxygen specieis, leukotrienes and toxic enzymes.
• The net effect of this is a prolonged decrease in airway function until the inflammation is resolved.

Question 19

Does histamine have a role in asthma?

Answer 19

No

In most allergies, histamine (another inflammatory mediator) released by mast cells plays a major role in the pathophysiological mechanism. However in asthma, histamine appears to have a very limited role. Whilst drugs which block histamine receptors (anti-histamines) are one of the primary treatments for allergies in general, they are ineffective at treating asthma

Question 20

What are the early and late phases in an asthmatic response to allergen?

Explain then

Answer 20

EARLY (0-1 hours)
With acute bronchoconstriction brought about by the initial phases wave of degranulation

LATE (up to 12 hours)
Symptoms initially improve before worsening brought about by secondary inflammation and the migration of Th2 and eosinophils.
Generates nighttime asthma and airway hyper responsiveness

Question 21

What do Eosinophils release?

Answer 21

Oxygen species, leukotrienes and toxic enzymes

Question 22

What is night time asthma?

Answer 22

Experience allergens in day and use inhaler then go to sleep and wake up with breathlessness

This occurs in late asthmatic response to antigen

Question 23

What is airway hyper responsiveness?

Answer 23

Level of allergen exposure required to induce an attack is much lower

This occurs in late asthmatic response to antigen

Question 24

What is the difference between obstructive and resistance for FEV1/FVC?

Answer 24

OBSTRUCTIVE
FEV1/FVC < 70% e.g. Asthma, increase resistance
Reduction of FEV1/FVC is proportional

RESTRICTIVE
FEV1/FVC > 80%
e.g. fibrosis which decreases compliance
FVC remains the same but FEV1 decreases

Question 25

What is airway modelling?

Answer 25

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

Repeated waves of inflammation and tissue damage may eventually result in long term irreversible reductions in airway function known as airway remodelling

Question 26

List some pathological changes in airway remodelling

Answer 26

• Smooth muscle hypertrophy
• Increased secretion of highly viscous mucus (goblet cell hyperplasia)
• Immune cell filtration
• Distrupted epithelium (easier access for allergens)
• Basement membrane thickening
• Fibrosis

Question 27

Is airway remodelling reversible?

Answer 27

No
One of the primary aims of treatment is to prevent degeneration of airway function via adequate control of symptoms and inflammation.

Question 28

What are the two primary first line pharamacological treatments for asthma?

Answer 28

1. Short acting B2 adrenergic receptor agonists e.g. salbutamol

• Provides acute relief in event of an asthma attack by relaxing ASM cells (bronchodilation)
• This increases airway lumen, decreases airway resistance so airflow increases.

2. Inhaled corticosteroids e.g. fluticasone

• Target and reduce the inflammatory component of the disease by acting on a range of cell types
• ISC act to modulate cytokine expression therefore inhibiting proliferation, activation and chemotaxis of leukocytes (e.g. B cells) however, ICS help to reduce mucus secretion by targeting goblet cells.

Question 29

List other pharmacological treatments for asthma (not main 2)

Answer 29

Leukotriene receptor antagonists (montelukast): inhibit effects of pro-inflammatory leukotriene mediators by blocking receptors.

Anti-IgE mAb (omalizumab): binds to circulating IgE, neutralising it, thus reducing its role in the pathological mechanism.

Anti-cytokine biologics (e.g. anti-Il-4, -Il-5 or -IL-13 mAb)
Muscarinic receptor antagonists (tiotropium): block muscarinic receptors inhibiting the effects of acetylcholine to thus reduce mucus secretion & relax ASM