Eicosanoids in the Airway

Question 1

Describe 3 features of allergic asthma

Answer 1

Chronic inflammation

Episodic reversible bronchoconstriction

Airway remodelling

Question 2

What is an eicosanoid and name two types.

Answer 2

Eicosanoids: oxygenated derivatives of 20-carbon fatty acids (eicosa = 20 in greek)

Arachidonic Acid (AA) can be broken down into:

1. Leukorienes (LT)
2. Prostanoids
   
   1. Prostaglandins PG
   2. Prostacyclins PGI
   3. Thromboxanes (Tx)

Question 3

Outline the biosynthesis of eicosanoids (including early enzymes)

Answer 3

Membrane phospholipid to AA is rate lmiting step

Question 4

Describe the synthesis of leukotrienes from arachidonic acid including enzymes invovled at each step and the receptors in which they act on.

Answer 4

Question 5

Which receptors do LTC4, LTD4, LTE4 act on?

What type of receptors are these?

In what stage of anaphylaxis are they involved in?

Answer 5

CysLT1R and CysLT2R

G protein-coupled receptors

Slow reacting (late phase)

Question 6

What receptor(s) does LTB4 act on?

What type of receptor(s) is this?

What is it invoved in?

Answer 6

BLT1 and BLT2

G protein-coupled receptors

Neutrophil (+other leukocytes) recruitment

Question 7

What four effects do leukotrienes have in asthma?

Answer 7

1. Bronchoconstriction (airflow obstruction)
2. Mucus hypersecretion
3. Inflammatory cell infiltration (eosinophils)
4. Plasma Exudation

Question 8

Name a:

Leukotriene antagonist

5-lipoxygenase inhibitor

Answer 8

Montelukast/SINGULAIR - Leukotriene antagonist

Zileuton - 5-LO inhibitor

• CysTL1R are sensitive to traditional antagonists whilst CysTL2R are not.*
• Leukotrienes are raised in mild-moderate asthma not severe*
• However, not all asthmatics respond to leukotriene therapy (GG/CT genotype?)*

Question 9

Aspirin-sensitive asthma (recently termed NERD - NSAID-exacerbated respiratory disease) affects 20% of asthmatics. Explain how this phenotype may arise.

Answer 9

Patients with NERD may have increased sensitivity to NSAIDs (increased COX1/2 response) in their mucosa compared to other asthmatics.

COX1/2 inhibition shifts eicosanoid production to leukotriene arm. LTs cause bronchoconstriction, mucus hypersecretion, inflammatory cell infiltration, plasma exudation.

?Can work otherway around - 5-LO inhibitors

Question 10

LTB4 is an attractive therapeutic target as excess production has been associated with chronic lung disease. Describe 4 effects of LTB4 in lung disease.

Answer 10

1. Potent chemoattractant for leukocytes
2. Activator and survival factor for cells tightly implicated in asthma
3. Promote proliferation and migration of ASM
4. Stimulate pro-inflammatory mediator release

Question 11

LTB4 therapy has been studied as there is an unmet medical need for the treatment of ______ asthma (It is thought LTB4 is the main chemoattractant in ______ recruitment). There is a high _____ in airway secretions in this subset of sever asthmatics, and are _____-resistant. LTB4 negatively correlates with FEV1. This has been the main speculation for the basis of LTB4 therapy.

Answer 11

LTB4 therapy has been studied as there is an unmet medical need for the treatment of neutrophilic asthma (It is thought LTB4 is the main chemoattractant in neutrophil recruitment). There is a high neutrophilia in airway secretions in this subset of sever asthmatics, and are steroid-resistant. LTB4 negatively correlates with FEV1. This has been the main speculation for the basis of LTB4 therapy.

Question 12

Describe whether LTC4S (LTC/D/E4), LTB4 and lipoxins are pro- or anti-inflammatory

Answer 12

LTC4S (LTC/D/E4): Pro-inflammatory

LTB4: Pro-inflammatory

Lipoxins: Anti-inflammatory

Question 13

Describe 3 possible pharmacological targets/approaches for LTB4 therapy

Answer 13

1. 5-Lipoxygenase/FLAP inihbition
2. BLT1/2 antagonists
3. LTA₄ hydrolase inhibitors

Question 14

Describe the positive and negative effects of 5-lipoxygenase/FLAP inhibition

Answer 14

Positive:

1. reduces LTA₄ levels (therefore reduced LTC/D/E₄

NEgative:

1. Reduces anti-inflammtory lipoxins
2. Poor patient compliance and extensive side effects

Question 15

Describe the positive and negative effects of BLT1 and BLT2 antagonists

Answer 15

Positive:

1. Blocks LTB4 signalling well

Negative:

1. Anti-inflmmatory mediators signal through BLT1 and BLT2
2. Potent BLT1 antagonists can act as partial agonists (therefore more inflammation)

Question 16

Describe the positive and negative effects of LTA₄ hydrolase inhibtiors

Answer 16

Positive:

1. Inhibits t rate limiting step for LTB₄ generation
2. Shown to promote lipoxin production

Negative:

1. LTA₄ hydrolase has secondary anti-inflammatory role - degrades PGP (pro-inflammtory/remodelling factor)

Question 17

Describe the biosynthesis of prostanoids with the relevant enxymes

Answer 17

Question 18

Which COX enzyjme is constitutive and inducible

Answer 18

COX 1 = constitutive

COX 2 = inducible (in inflammation)

Question 19

Which prsotaglandins cause bronchoconstriction?

Answer 19

PGD₂

PGF_2α

TXA₂

Question 20

Which prostanoids cause increased airway secretion?

Answer 20

PGD₂

PGE₂

PGF_2α

Question 21

Which prostanoids cause bronchodilation?

Answer 21

PGE₂

Question 22

Which receptors do PGD₂ bind to and which is asscoaited with innate lymphoid cell signalling

Answer 22

DP1

DP2 (CRTH2) - innate lymhoid cell sgnalling

Question 23

PGE₂ has bronchodilater/protective and anti-inflammatory effects. It also has one major side effect. Name the receptors involved in these three effects.

Answer 23

Bronchodilator: EP4

Anti-inflammatory: EP4

Cough: EP3 (in guinea pigs) (vagus nerve?)

PGE2 potential therapy - EP4 agonists in combination with EP3 antagonists to relieve the cough effect)