34 - Lipid Mediators

Question 1

Arachidonic acid

Answer 1

Precursor for many bioactive lipids

Also called C20:4 (20 carbons, 4 double bonds), eicosatetraenoid acid.

Question 2

How does the body get arachidonic acid?

Answer 2

From dietary poly-unsaturated fatty acids
Indirectly as linoleic acid, which is converted to arachidonic acid.
Directly as arachidonic acid

Question 3

Type of fat that arachidonic acid is

Answer 3

Omega-6-polyunsaturated acid

Question 4

How is arachidonic acid stored?

Answer 4

Stored esterified in membrane phospholipids (plasma, nuclear membranes)

Question 5

How is arachidonic acid released from cell membranes?

Answer 5

Phospholipase A2 releases arachidonic acid.

Phospholipase A2 is activated by increased intracellular Ca2+ or ERK (extracellular receptor kinase)

Question 6

Part of arachidonic acid pathway that is tightly regulated

Answer 6

Phospholipase A2 activation. If not controlled, can have excessive bradykinins and leukotrienes produced.

Question 7

Component of many snake venoms

Answer 7

Phospholipase A2

Question 8

Name for biologically-active metabolites of arachidonic acid

Answer 8

Eicosanoids

Question 9

What determines eicosanoid type?

Answer 9

Which type of enzyme metabolises arachidonic acid

Question 10

Enzymes that can metabolise arachidonic acid
1)
2)
3)

Answer 10

1) Cyclo-oxygenase I (COXI) - constitutively expressed
2) COXII - Inducible by inflammatory stimuli (EG: IFN)
3) Lipoxygenase (expressed in inflammatory cells, eosinophils, mast cells)

Question 11

Effect of arachidonic acid metabolism by COXI

Answer 11

Physiological prostaglandin production

Question 12

Effect of arachidonic acid metabolism by COXII

Answer 12

Patho-physiological prostaglandin production

Question 13

Intermediate stage between arachidonic acid and stable prostaglandins?

Answer 13

Cyclic endoperoxidases (very unstable).
These are quickly converted to stable prostaglandins by peroxidases.

Question 14

Nomenclature of stable prostaglandins

Answer 14

Letter describes ring structure.

Number describes number of double bonds

Question 15

PGE2 
1)
2)
3)
4)

Answer 15

1) Relaxes vascular smooth muscle
2) Hyperalgesic
3) Pyrogenic
4) Angiogenic (wound healing, tumour growth)

Question 16

Prostaglandins that are bronchoconstrictors

Answer 16

PGD, PGF2alpha

Question 17

Site of action of prostaglandins

Answer 17

Very local.
Degraded by endothelial cells of pulmonary capillaries.
Unstable, don’t last more than a few minutes.

Question 18

Main indications of NSAIDS
1)
2)
3)

Answer 18

1) Analgesic
2) Antipyretic
3) Anti-inflammatory

Question 19

Effect of PGE2 on blood flow

Answer 19

Increases blood flow

Question 20

Local mediators that increase vascular permeability

Answer 20

Histamine, bradykinin

Question 21

Difference in hyperalgesia induced by bradykinins and prostaglandins

Answer 21

Bradykinins are directly painful.

Prostaglandins enhance sensitivity to pain, but aren’t painful in and of themselves

Question 22

Long-term interaction between IL-1b and arachidonic acid pathways
1)
2)

Answer 22

1) IL-1b induces increase in bradykinin receptors,

2) Increased COXII, phospholipase A2 levels

Question 23

Factor responsible for core temperature rise in fever

Answer 23

PGE2

Question 24

PGE2 effects on the gut
1)
2)
3)
4)

Answer 24

1) Promotes blood flow (vasodilation)
2) Promotes angiogenesis
3) Increases mucus secretion
4) Reduces gastric acid secretion

Question 25

How can chronic NSAID use lead to gastric ulcers?

Answer 25

PGE2 protects the gut by promoting blood flow (increased healing), increasing mucus secretion and reducing gastric acid secretion in the gut). NSAIDS inhibit PGE2 formation, so there is no more gastric protection by it

Question 26

Characteristic chemical structure in prostaglandins

Answer 26

Cyclopentane ring

Question 27

Prostacyclin effects 1) 2)

Answer 27

1) Vasodilator | 2) Reduces platelet activation

Question 28

Prostacyclin half life

Answer 28

Very short. | T1/2 is about 3 minutes

Question 29

Thromboxane A2 effects 1) 2)

Answer 29

1) Increases platelet activation | 2) Vasoconstrictor

Question 30

Thromboxane A2 half life

Answer 30

Very short. | About 30 seconds

Question 31

Two opposing factors controlling platelet aggregation

Answer 31

Thromboxane A2 and prostacyclin

Question 32

Cells that produce prostacyclin

Answer 32

Endothelial cells

Question 33

Cells that produce thromboxane A2

Answer 33

Platelets

Question 34

Thromboxane A2 function in clotting

Answer 34

Platelets release thromboxane in a positive feedback loop. The more platelets near each other, the more thrmoboxane is released, and the more vasoconstriction and platelet activation occur

Question 35

Factor that promotes coronary artery disease

Answer 35

Thromboxane A2

Question 36

Factor that protects against coronary artery disease

Answer 36

Prostacyclin

Question 37

Another name for prostacyclin

Answer 37

PGI2

Question 38

How does aspirin protect against heart disease? 1) 2) 3)

Answer 38

1) Aspirin covalently binds COX, inactivates it. 2) Endothelial cells can replenish COX as they are nucleated. Therefore they can continue releasing prostacyclin (takes a few hours to re-synthesise COX). 3) Platelets can't replenish COX, as they don't have a nucleus. Therefore can make more thromboxane for the rest of their lifespan (~8 days)

Question 39

Effect of aspirin on lipoxygenase

Answer 39

Increases activity of lipoxygenase. Therefore when aspirin is administered, there is an increase in anti-inflammatory arachidonic acid derivatives ('aspirin-triggered lipoxins')

Question 40

Aspirin-triggered lipoxins

Answer 40

Analogues of normally-triggered lipoxins. | Generated from aspirin-mediated enhancement of lipoxygenase activity

Question 41

Why are omega-three fatty acids considered beneficial to health?

Answer 41

Replace arachidonic acid derivatives with those from omega3 fatty acids. These derivatives are converted to prostacyclin at the same level, but much less thromboxane A2 is produced.

Question 42

How are leukotrienes formed? 1) 2) 3)

Answer 42

1) Arachidonic acid is metabolised by 5-lipoxygenase instead of COX. 2) 5-lipoxygenase converts arachidonic acid to 5-HPETE. 3) 5-HPETE converted to leukotrienes

Question 43

5-lipoxygenase cell distribution

Answer 43

Only known to be made by inflammatory cells

Question 44

5-lipoxygenase function

Answer 44

Only known function is inflammation

Question 45

``` LTA4 1) 2) 3) 4) ```

Answer 45

1) Bronchoconstrictor 2) Vasoactive - leads to tissue oedema. 3) Implicated in asthma 4) Derived from 5-PETE.

Question 46

Leukotriene B4

Answer 46

No direct action on smooth muscle | Promotes inflammation by attracting leukocytes

Question 47

How do glucocorticoids work?

Answer 47

Induces annexin-1, which inhibits phospholipase A2

Question 48

Leukotriene receptor antagonist

Answer 48

Montelukast