Asthma

Question 1

How does inflammation cause airway dysfunction? (briefly)

Answer 1

→ Allergen inhalation
→ Immune system response
→ Airway inflammation
→ Impaired airway function
→ Wheezing, coughing, dyspnoea

Question 2

What lifestyle factors make it more likely to get asthma?

Answer 2

→ Urban dwelling
→ Pollution
→poor diet
→ obesity

Question 3

What is Ohms law?

Answer 3

→ Airflow is proportional to 1/resistance

Question 4

What does the Hagen-Poiseuille law state?

Answer 4

→ As an airways radius decreases the resistance increases and airflow decreases dramatically

Question 5

What determines the radius of the lumen?

Answer 5

→ The level of contraction of smooth muscle

Question 6

What factors decrease the radius of the lumen even further?

Answer 6

→ Hypersecretion of mucus

→ Swelling

Question 7

What is wheezing caused by?

Answer 7

→ Turbulent airflow

→ Increases resistance and decreases airflow

Question 8

What is the first stage in the allergic response?

Answer 8

→sensitization
→ person breathes in allergen
→ Gets stuck in the airways
→ APC recognizes allergen as being harmful
→ Processes antigen to a helper T cell
→T cells mature and become TH2 cells
→ TH2 cells secrete cytokines like IL5
→ IL4 interacts with B cells and stimulates them
→ B cells proliferate and produce IgE antibodies
→ Antibodies bind to mast cells

Question 9

What is the second stage in the allergic response?

Answer 9

→ Exposure
→ Allergen binds to antibodies
→ Mast cells degranulate
→Prostaglandins, LTs and chemokines are secreted
→ Mediators bind to receptors
→cause smooth muscle to contract
→ Mediators attract TH2 and eosinophils
→ Eosinophils migrate to airways and release reactive O2 species
→ Second round of inflammation occurs

Question 10

What is the early phase of the asthmatic response?

Answer 10

→ Initial degranulation of mast cells

→ After the first response the mediators are cleared and effects resolve themselves

Question 11

What is the secondary phase of the asthmatic response?

Answer 11

→ Eosinophils and T cells being recruited several hours later

Question 12

What are the changes in respiratory function observed in asthma?

Answer 12

→ FEV1 decreases
→ FVC is unchanged
→ FEV/FVC decreases <70%

Question 13

What are the long term changes caused by uncontrolled asthma?

Answer 13

→ Smooth muscle is being constantly worked
→ Hypertrophy of smooth muscle
→ More muscle takes up more space and contracts harder
→ More goblet cells and mucus glands
→ Infiltration of immune cells
→ Epithelium Distruption
→ Basement Membrane thickening
→ ECM deposition and Fibrosis

Question 14

What are the most effective treatments for asthma?

Answer 14

→ Beta 2 agonists and corticosteroids

Question 15

What happens during sensitisation?

Answer 15

→the allergen is inhaled and enters the airway tissue
→stimulates parts of the innate immune system, such as the epithelium
→allergen is them encountered by antigen presenting cells (APCs), such as dendritic cells and macrophages

Question 16

How is class switching initiated?

Answer 16

→The activated Th2 cell then interacts with a B cell to initiate class-switching

Question 17

What do the released IgE do?

Answer 17

circulate and bind (via their heavy chain/Fc region) to IgE (FcεRI) receptors on granulocytes such as mast cells

Question 18

What does IL-5 particularly do?

Answer 18

promotes survival, proliferation and trafficking (e.g. to the airways) of eosinophil

Question 19

What is the result of inflammatory responses?

Answer 19

rapid bronchospasm and a sharp decrease in airflow

Question 20

What role does histamine play in asthma?

Answer 20

→histamine release from mast cells appears to play a very limited role in the pathophysiology of asthma

Question 21

What do eosinophils release?

Answer 21

reactive oxygen species, leukotrienes and proteolytic enzymes

Question 22

What is hyper-responsiveness?

Answer 22

a period where the threshold of allergen exposure required to elicit further asthma attacks is greatly reduced

Question 23

What is airway remodelling?

Answer 23

→the inflammation triggered within the airway can result in tissue injury as the noxious mediators released from immune cells cause cellular damage.
→the cycles of tissue injury and repair can lead to irreversible structural changes
(↑obstruction, ↓FEV1, respiratory failure

Question 24

What are some structural changes that can occur due to repeated asthma cycles?

Answer 24

fibrosis, smooth muscle hypertrophy, goblet cell hyperplasia, epithelium disruption

Question 25

How does activation of epithelial generate local inflammation?

Answer 25

the release of alarmins, epithelial-derived mediators (TSLP, IL-25, IL-33) that prime antigen presenting cells and trigger downstream inflammatory responses.

Question 26

What are type-2 innate lymphoid cells?

Answer 26

→ILC2s are similar to Th2 cells (in terms of their role in releasing cytokines
→but lack lymphocyte surface markers and antigen-specific receptors

Question 27

How are ILC2s activated?

Answer 27

activated by alarmins, triggering release of the type 2 cytokines IL-5 and IL-13.

Question 28

How do beta agonists work?

Answer 28

activation (agonism) of beta-2 adrenergic receptors present in the membrane of airway smooth muscle cells
→induces a signalling cascade that increases production of cAMP
→ activation of protein kinase A, which reduces Ca2+ mobilisation, inducing relaxation

Question 29

What are short acting beta-2 agonists?

Answer 29

such as salbutamol are the first-line therapy in asthma and are administered when required as reliever therapy

Question 30

What are long-acting beta-2 agonists?

Answer 30

such as salmeterol or formoterol are used as an add-on, preventer treatment, in combination with inhaled corticosteroids
→because there is evidence that the use of LABAs without corticosteroids increases the risk of sudden death

Question 31

What are long acting muscarinic receptor antagonists?

Answer 31

→bronchodilators
→widely used to treat chronic bronchitis in COPD patients,
→dosed on a daily, continual basis via metered-dose inhalers

Question 32

How do LAMAs work?

Answer 32

involves blocking acetylcholine receptors present on ASM cells.
→blockade of this receptor reduces the level of contraction
→may also provide benefit in patients with obstructive airway diseases by reducing mucus secretion and inhibiting cough

Question 33

Examples of corticosteroids?

Answer 33

fluticasone, beclometasone, and budesonide

Question 34

How is corticosteroid helpful?

Answer 34

Reduction in inflammatory cells and their numbers:
cytokines, mast cells, dendritic cells

Structural cells:
→endothelial cell leak
→increased beta-2 receptors
reduced mucus secretion

Question 35

How do corticosteroids achieve their anti-inflammatory effect?

Answer 35

by binding to glucocorticoid receptors present within the cytosol of immune and structural cells
→ bound drug-receptor complex then migrates to the nucleus of the cell where it binds to DNA, modulating transcription, translation, and protein expression

Question 36

How do leukotriene antagonists like montelukast work?

Answer 36

Competitive antagonism (blockade) of leukotriene receptors, by which pro-inflammatory LT mediators act.