Pathophysiology of asthma

Question 1

Define asthma

Answer 1

chronic inflammatory condition categorised by episodes of reversible airflow limitation + bronchial hyperresponsiveness, where difficulty breathing (dyspnoea)

Question 2

How can asthma be divided?

Answer 2

Inflammation

Airway dysfunction

Question 3

How does the inflammatory response to asthma start?

Answer 3

hypersensitivity to stimulus (allergen - pollen, house dust mites)

Question 4

Describe airway dysfunction of asthma

Answer 4

allergen-induced inflammation release mediators
affecting cellular function, produce limitations in tissue function (airflow) –> symptoms (dyspnoea, excess mucus, cough)

Question 5

What happens to the airways during an asthma attack?

Answer 5

• inflammation –> pathological changes
• smooth muscle contraction + mucus hypersecretion
• reducing lumen size
• increases airway resistance + decreases airflow

Question 6

What are the stages of allergic asthma?

Answer 6

Sensitisation

Allergic response

Question 7

What’s sensitisation

Answer 7

immune system 1st encounters allergen + develops an

adaptive (antibody lymphocyte-mediated) immune response

Question 8

What’s an allergic response

Answer 8

allergen re-encountered, triggering adaptive response generating inflammatory response within airways producing symptoms

Question 9

Describe the process of sensitisation

Answer 9

-allergen enters airways
-stimulates epithelium releasing proinflammatory signals
-APCs (dendritic cells + macrophages) engulf + process allergen
-presents antigen to naïve (CD4+) Th
-activated, matured into Th2
-interacts w B cell, initiating class-switching,proliferation, production of IgE
-bind the antigen in allergen
-circulate, bind (via heavy chain/Fc region) to IgE
(FcεRI) receptors on mast cells
-light chain/Fab region still displayed for antigen binding
-Th2 cells secrete ‘Th2 cytokines’ : IL-4, IL-5, IL-13,
-modulates immune system
-IL-5 promotes survival, proliferation, trafficking (to airways) of eosinophils

Question 10

How does Th mature into Th2?

Answer 10

depending on the cytokine environment- levels of inflammatory mediators (IL-4 +TNF-∝)

Question 11

Define class-switching

Answer 11

class of Ig antibody the B cell produces

Question 12

Role of mast cells?

Answer 12

immune cells has responses to parasitic helminths infections, contain granules containing pro-inflammatory mediators such as histamine, leukotrienes, prostaglandins

Question 13

What are eosinophils + role?

Answer 13

polymorphonuclear granulocyte

parasite defence that’s heavily implicated in asthma

Question 14

Describe allergic repsonse process

Answer 14

• re-exposure
• antigens recognised by IgE bound to mast cells within the airways
• multiple IgE molecules cross-linked by allergen
• triggers degranulation
• granulocyte releases contents of inflammatory mediators
• binds to receptors on multiple cell types in airway inducing pathological changes
• contraction of airway smooth muscle cells, microvascular leak (oedema), activation of goblet cells (mucus secretion)
• bronchospasm
• mediators also induce secondary proinflammatory changes
• Th2 + eosinophils activated
• triggering wave of inflammation as they migrate to airways + release further pro-inflammatory mediators

Question 15

eg of inflammatory mediators in granulocytes?

Answer 15

prostaglandins, leukotrienes, cytokines

Question 16

Immediate effect of pathological changes?

Answer 16

rapid bronchospasm =sharp decrease in airflow (due to airway resistance).

Question 17

Why are anti-histamines ineffective in treating asthma?

Answer 17

histamine released from mast cells have small role in the pathophysiology of asthma

Question 18

What do Th2 release?

Answer 18

IL-4, IL-5, IL-13,

Question 19

What do eosinophils release?

Answer 19

reactive oxygen species, leukotrienes, toxic enzymes

Question 20

Phases of airway dysfunction?

Answer 20

Early response (0-1 hrs)
Late response

Question 21

Describe early response of asthma attack

Answer 21

• (0-1 hrs) w acute bronchoconstriction by initial wave of degranulation,
• extended period (<12 hours)- symptoms improve before worsening

Question 22

Describe late response of asthma attack

Answer 22

• secondary inflammation

- migration of Th2 + eosinophils to airways

Question 23

What contributes to night-time asthma?

Answer 23

Early + late asthmatic responses

Question 24

What’s night-time asthma?

Answer 24

worse symptoms at night, during sleep causing them to wake up

Question 25

Define airway remodelling

Answer 25

long term irreversible reductions in airway function due to repeated waves of inflammation + tissue damage

Question 26

What are the pathological changes of airway remodelling?

Answer 26

smooth muscle hypertrophy, increased secretion of highly-viscous mucus, goblet
cell hyperplasia, immune cell infiltration, disrupted epithelium (enabling greater infiltration of allergens), basement membrane thickening, fibrosis

Question 27

What does Anti-IgE mAb (omalizumab) affect?

Answer 27

Antibody binds IgE

Question 28

What does Corticosteroids (fluticasone) affect?

Answer 28

Airway inflammation

Question 29

What does Leukotriene receptor antagonists (montelukast) affect?

Answer 29

Airway inflammation

Question 30

What does IL-4, IL-5, IL-13 mAb affect?

Answer 30

Airway inflammation

Question 31

What does β2 adrenergic receptor agonists (salbutamol) affect?

Answer 31

Airway smooth muscle contraction

Question 32

What does Muscarinic receptor antagonists (tiotropium) affect?

Answer 32

Airway smooth muscle contraction

Mucus secretion

Question 33

What does Corticosteroids affect?

Answer 33

Mucus secretion

Oedema

Question 34

Why are specific treatments not always effective?

Answer 34

asthma is a complex + heterogeneous condition w multiple endotypes